Sassafras

Summary and Pharmaceutical Comment

In addition to its traditional herbal use for treating dermatological and rheumatic ailments, sassafras also used to be a common flavouring ingredient in beverages, in particular root beer. However, animal studies have revealed the carcinogenic and hepatotoxic potential of safrole, the major component of sassafras volatile oil. Consequently, the use of safrole is no longer permitted in foods and sassafras is not permitted as an ingredient in licensed medicinal products.

Antiseptic and diuretic properties claimed for sassafras are probably attributable to the volatile oil, although no documented studies were found supporting the antirheumatic claims. Sassafras should not be used as a herbal remedy, either internally or externally.

Species (Family)

Sassafras albidum (Nutt.) Nees (Lauraceae)

Synonym(s)

Ague Tree, Cinnamon Wood, Saloop, Sassafras sassfras (L.) Karst., S. albidum var. molle (Raf.) Fern., Saxifrax

Part(s) Used

Inner root bark

Pharmacopoeial and Other Monographs

BHP 1983(G7)

Martindale 35th edition(G85)

Legal Category (Licensed Products)

Sassafras is not permitted for use in medicinal products.

Constituents

SThe following is compiled from several sources, including General Reference G2.

Alkaloids Isoquinoline-type about 0.02%. Boldine, isoboldine, norboldine, cinnamolaurine, norcinnamolaurine and reticuline.

Volatile oils 5–9%. Safrole as major component (80–90%), others include anethole, apiole, asarone, camphor, caryophyllene, coniferaldehyde, copaene, elemicin, eugenol, 5-methoxyeugenol, menthone, myristicin, a-pinene, a- and b-phellandrene, piperonylacrolein and thujone.

Other constituents Gum, mucilage, lignans (sesamin, desmethoxyaschantin), resin, sitosterol, starch, tannins and wax.

Food Use

Sassafras oil was formerly used as flavouring agent in beverages including root beer.(G58) However, in the 1960s safrole, the major

component of the volatile oil, was reported to be carcinogenic.(G58) The use of safrole in foods is now banned, and its use in

Figure 1 Selected constituents of sassafras.

toilet preparations controlled.(G45) Previously, in the USA, safrolefree sassafras extract, leaf and leaf extract have been approved for food use. In 1976, the US Food and Drugs Administration (FDA) banned interstate marketing of sassafras for sassafras tea.(G22)

Herbal Use

Sassafras is stated to possess carminative, diaphoretic, diuretic, dermatologic and antirheumatic properties. Traditionally, it has

been used for cutaneous eruptions, gout and rheumatic pains.(G2,

G7, G64)

Dosage

Dosages for oral administration (adults) for traditional uses recommended in standard herbal reference texts are given below. However, sassafras is no longer recommended for internal or external use.

Bark 2–4 g as an infusion three times daily.(G7)

Liquid extract 2–4 mL (1 : 1 in 25% alcohol) three times daily.(G7)

Pharmacological Actions

Studies have concentrated on investigating the toxicity associated with the bark. However, aqueous and alcoholic extracts have been reported to elicit ataxia, hypersensitivity to touch, CNS depression and hypothermia in mice.(1) Both inhibition and induction of hepatic microsomal enzymes have been documented for safrole.(2, 3) Enzyme-inducing activity was found to be a transient phenomenon, with activity falling after the onset of hepatic toxicity (see Side-effects, Toxicity).(2) Safrole is reported to induce both cytochrome P488 and P450 activities. Sassafras oil has been used as a topical antiseptic, pediculicide and carminative.(4)

Figure 2 Sassafras (Sassafras albidum).

Side-effects, Toxicity

Clinical data

The toxicity of sassafras is attributable to the volatile oil, and in particular to the safrole content. It is estimated that a few drops of sassafras oil are sufficient to kill a toddler and as little as one teaspoonful has proved fatal in an adult.(5) Symptoms of

poisoning are described as vomiting, stupor and collapse. High doses may cause spasm followed by paralysis.(G58) Large amounts

of the oil are reported to be psychoactive with the hallucinogenic effects lasting for several days.(G22) One of the components of the

oil is myristicin, the hallucinogenic principle in nutmeg. Sassafras has traditionally been used as an ingredient of beverages. To put the potential toxicity of sassafras into perspective, the following estimation has been made.(1) Extrapolation of results from animal toxicity studies indicate that 0.66 mg/kg may prove hazardous in humans.(1) By comparison, a cup of sassafras tea, prepared from a 2.5 g teabag, may provide up to 200 mg safrole, representing approximately 3 mg/kg.(1)

Figure 3 Sassafras – dried drug substance (inner root bark).

Preclinical data

Safrole, the principal component of the volatile oil, was first recognised to be a hepatocarcinogen in the 1960s(6) and many animal studies have been documented concerning this toxicity.(7) Both benign and malignant tumours have developed in laboratory animals, depending on the dose of safrole administered.(2)

Both human and animal studies have shown that safrole gives rise to a large number of metabolites.(8) A sulfate ester (formed via a hydroxylated metabolite) has been established as the ultimate carcinogen for safrole with tumour incidence paralleling the rate of conversion to the ester.(9) Induction of cytochrome P450 activity has been associated with mutagenic and carcinogenic activity of the inducing agent.(10) The inducing effect of safrole on certain metabolising enzymes is thought to play a role in the carcinogenic activity of safrole. The liver has a high level of cytochrome P450 activity and is therefore susceptible to induction.(10)

Acute oral LD50 values for safrole have been reported as 1.95 g/ kg (rats) and 2.35 g/kg (mice).(2) Major symptoms of toxicity are

stated as ataxia, depression, diarrhoea, followed by death within four hours to seven days.(11) Rats fed safrole in their diet at

concentrations of 0.25, 0.5 and 1.0% exhibited reduction in growth, stomach and testicular atrophy, liver necrosis, biliary proliferation and primary hepatomas.(G22) Animals have also developed tumours when fed safrole-free extracts.(G22)

Conflicting results have been reported from studies investigating the mutagenicity of safrole, using the Ames test and DNA repair test.(12, 13) Purity of the safrole, test system employed, type of metabolic activation mix, and toxicity of the test system have been suggested as reasons for the observed variations.(12)

Contra-indications, Warnings

Sassafras should not be used internally or externally. Safrole, the major component in the volatile oil of sassafras, is hepatotoxic and even safrole-free extracts of sassafras have been reported to

produce tumours in animals. Sassafras essential oil is contraindicated in internal and external use.(G58) Sassafras has been

reported to inhibit and induce microsomal enzymes.

Pregnancy and lactation Sassafras is contra-indicated during pregnancy and lactation. The oil is reported to be abortifacient.(5)

References

3Jaffe H et al. In vivo inhibition of mouse liver microsomal hydroxylating systems by methylenedioxyphenyl insecticidal synergists

and related compounds. Life Sci 1968; 7: 1051–1062.

4 International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. Some Naturally Occurring Substances, vol 10. Geneva: WHO, 1976.

5Craig JO. Poisoning by the volatile oils in childhood. Arch Dis Child 1953; 28: 475–483.

6Homburger F, Boger E. The carcinogenicity of essential oils, flavors, and spices: A review. Cancer Res 1968; 28: 2372–2374.

7 Opdyke DLJ. Sassafras oil. Food Cosmet Toxicol 1982; 20: 825–826.

8Ioannides C et al. Safrole: its metabolism, carcinogenicity and interactions with cytochrome P-450. Food Cosmet Toxicol 1981; 19:

657–666.

9Bock KW, Schirmer G. Species differences of glucuronidation and sulfation in relation to hepatocarcinogenesis. Arch Toxicol 1987; 10 (Suppl. Suppl.): 125–135.

520 Sassafras

10Iwasaki K et al. Induction of cytochrome P-448 activity as exemplified by the O-deethylation of ethoxyresorufin. Effects of dose, sex, tissue and animal species. Biochem Pharmacol 1986; 35: 3879–3884.

11Jenner PM et al. Food flavourings and compounds of related structure. I. Acute oral toxicity. Food Cosmet Toxicol 1964; 2: 327–343.

12Sekizawa J, Shibamoto T. Genotoxicity of safrole-related chemicals in microbial test systems. Mutat Res 1982; 101: 127–140.

13Swanson AB et al. The mutagenicities of safrole, estragole, eugenol, trans-anethole, and some of their known or possible metabolites for

Salmonella typhimurium mutants. Mutat Res 1979; 60: 143–153.

Summary and Pharmaceutical Comment

The chemistry of saw palmetto is well-documented. Several pharmacological activities have been described for saw palmetto in vitro and in vivo (animals). Some of these properties, such as inhibition of 5-a-reductase activity, inhibition of androgen binding and spasmolytic activity, are thought to explain, at least in part, the effects of saw palmetto in benign prostatic hyperplasia (BPH). However, some experimental and clinical studies report conflicting results, particularly with regard to the inhibition of 5-a- reductase activity and a-adrenoceptor blocking activity by saw palmetto extracts. Thus, the mechanism(s) of action of saw palmetto extracts in BPH remain unclear. This is not surprising, given that, at present, the exact cause of BPH is unknown. In addition to the effects of saw palmetto in experimental models of BPH, immunostimulant and antiinflammatory activities have been documented in laboratory studies.

BPH is not an indication suitable for self-diagnosis and selftreatment, and over-the-counter use of saw palmetto extract for BPH should be under medical supervision.

Collectively, evidence from clinical trials of saw palmetto products indicates that preparations containing saw palmetto improve urinary symptoms and flow measures in men with BPH and that improvement is similar to that achieved with finasteride.

Data from randomised clinical trials and post-marketing surveillance studies indicate that, generally, saw palmetto is well-tolerated; typically, adverse events reported are mild and relate mainly to gastrointestinal symptoms. Use of saw palmetto preparations at doses higher than those recommended for therapeutic effects should be avoided; further information is required on the safety of saw palmetto with long-term use (more than one year). There is a lack of information of the safety of saw palmetto when taken by women (e.g. for acne). In view of the documented pharmacological actions of saw palmetto preparations, the potential for interactions with other medicines administered concurrently, particularly those with similar or opposing effects, should be considered. Studies have assessed the effects of combination preparations containing saw palmetto, as well as different manufacturers’ products (which vary qualitatively and quantitatively in their phytochemical composition); at least eight studies involved one particular saw palmetto product. These points should be taken into account when considering the evidence to support the efficacy and safety of individual products. PC-SPES, a combination preparation containing saw palmetto fruit extract and seven other herbal ingredients, has been found to be adulterated with diethylstilbestrol, indometacin (indomethacin), warfarin and ethinylestradiol.

Species (Family)

Serenoa repens (W. Bart.) Small (Arecaceae/Palmae)

Synonym(s)

Sabal, Sabal serrulata (Michx.) Schult. f., Serenoa, Serenoa serrulata (Michx.) Hook. f. ex B.D. Jacks

Part(s) Used

Fruit

Pharmacopoeial and Other Monographs

BHP 1996(G9)

BHMA 2003(G66)

BP 2007(G84)

BPC 1934(G10)

Complete German Commission E(G3)

ESCOP 2003(G76)

Martindale 35th edition(G85)

Ph Eur 2007(G81)

USP29/NF24(G86)

Legal Category (Licensed Products)

GSL(G37)

Constituents

Carbohydrates Invert sugar 28.2%, mannitol, high molecular weight polysaccharides (e.g. MW 100 000) with galactose, arabinose and uronic acid(1) identified as main sugar components for one.

Fixed oils 26.7%. Many free fatty acids and their glycerides. Monoacylglycerides (1-monolaurin, 1-monomyristicin).(2) Oleic acid (unsaturated) and capric acid, caproic acid, caprylic acid, lauric acid, myristic acid, palmitic acid and stearic acid (saturated).

Most commercial preparations of saw palmetto contain lipophilic extracts.(G56)

Figure 1 Selected constituents of saw palmetto.

522 Saw Palmetto

Quality of plant material and commercial products

As with other herbal medicinal products, there is variation in the qualitative and quantitative composition of saw palmetto crude plant material and commercial preparations of saw palmetto fruit. Analysis of 14 saw palmetto products marketed in Europe and the USA for content of specific groups of constituents using liquid and gas chromatography revealed substantial variations in the concentrations of constituents present in different products.(6) Free fatty acid content ranged from 40.7% (in one product which contained 50% olive oil) to 80.7%, content of methyl and ethyl esters ranged from 1.5% (in one product which contained 50% olive oil) to 16.7%, long-chain esters from 0.7% to 1.4% and glycerides from 6.8% to 52.2% (in one product which contained 50% olive oil). Although it is clear that there are variations between products, data from this analytical study are difficult to interpret as values for actual content of the respective constituents were not reported.

Food Use

Saw palmetto is not used in foods. Previously, saw palmetto has

been listed by the Food and Drugs Administration (FDA) as a Herb of Undefined Safety.(G41)

Herbal Use

Saw palmetto is stated to possess diuretic, urinary antiseptic, endocrinological and anabolic properties. Traditionally, it has been used for chronic or subacute cystitis, catarrh of the genitourinary tract, testicular atrophy, sex hormone disorders and specifically for prostatic enlargement.(G7, G32, G64) Modern interest in saw palmetto is focused on its use in the treatment of symptoms of benign prostatic hyperplasia (BPH).

Dosage

Dosages for oral administration (adults) for traditional uses recommended in older standard herbal reference texts are given below.

Dried fruit 0.5–1.0 g as a decoction three times daily.(G7)

Extract 320 mg lipophilic ingredients extracted with lipophilic solvents (hexane or ethanol 90% v/v).(G3)

Clinical trials have assessed the effects of lipophilic extracts (containing lipids and sterols) of saw palmetto usually at a dosage

Sof 160 mg twice daily.

Figure 2 Saw palmetto (Serenoa repens).

Figure 3 Saw palmetto – dried drug substance (fruit).

Pharmacological Actions

In vitro and animal studies

Several pharmacological activities have been documented for saw palmetto in vitro and in vivo (animals). Several of these properties, such as inhibition of 5-a-reductase activity, inhibition of androgen binding and spasmolytic activity, are thought to explain, at least in part, the effects of saw palmetto in BPH. However, the clinical significance of the in vitro inhibition of 5-a- reductase activity by saw palmetto has not been clearly established (see Clinical studies).

5-a-Reductase is the enzyme that catalyses the conversion of testosterone to 5-a-dihydrotestosterone (DHT) in androgen target tissues, including the prostate. DHT is more potent than testosterone, and is thought to be implicated in the development of BPH. There is evidence that 5-a-reductase activity is higher in cells obtained from BPH tissue than from normal prostate tissue.

A lipidic (liposterolic) extract of saw palmetto was found to inhibit 5-a-reductase-mediated conversion of testosterone to dihydrotestosterone, and 3-ketosteroid reductase-mediated conversion of dihydrotestosterone to an androgen derivative.(5) Other in vitro studies have shown that an ethanolic extract of saw palmetto (IDS-89) inhibited 5-a-reductase activity in the epithelium and stroma of human BPH tissue in a concentrationdependent manner.(7) The IC50 was around 2.2 mg/mL. This study also demonstrated that the inhibitory effect of IDS-89 was mainly due to the fatty acid constituents of a saponifiable subfraction of the extract, as non-saponifiable and hydrophilic subfractions showed little or no inhibition of 5-a-reductase activity. Inhibition of 5-a-reductase by a liposterolic extract of saw palmetto has also been documented in porcine prostatic microsomes.(8)

There are at least two isoenzymes of 5-a-reductase (5-a- reductase types I and II), and several studies have documented that a liposterolic extract (Permixon) of saw palmetto inhibits both isoenzymes in prostate epithelial cells(9, 10) and fibroblast cells.(10) Several other studies have documented inhibition of 5-a-reductase activity by liposterolic extracts of saw palmetto in vitro.(5, G50) Permixon was reported to inhibit 5-a-reductase activity without affecting the secretion of prostate-specific antigen (PSA) by epithelial cells, suggesting that use of saw palmetto extract should

not interfere with PSA measurements for prostate-cancer screening.(9)

Anti-androgenic activity has been documented for a hexane liposterolic extract (Permixon) of saw palmetto. In vitro studies in rat prostate tissue and human foreskin fibroblasts indicated that

this extract competitively inhibited the binding of dihydrotestosterone to cytosolic and nuclear androgen receptor sites.(11, 12) By contrast, an alcoholic extract of saw palmetto appeared to be without androgen receptor-binding activity.(13)

Liposterolic extracts of saw palmetto have also been investigated in animal models of BPH. A liposterolic extract (Permixon) of saw palmetto 50 mg/kg body weight administered for 30 days to castrated rats with estradiol/testosterone-induced prostate enlargement resulted in significant reductions in the wet weight of the dorsal region of the prostate, compared with control.(14) Another study in rats compared the effects of a liposterolic extract of saw palmetto with those of the 5-a-reductase inhibitor finasteride in rat prostate hyperplasia induced by hyperprolactinaemia.(15) It was reported that the liposterolic extract of saw palmetto inhibited rat prostate hyperplasia in the lateral lobe induced by hyperprolactinaemia, and that finasteride did not antagonise the action of prolactin. By contrast, a study in dogs with BPH reported a lack of effect for saw palmetto extract on prostatic weight, prostatic volume, prostatic histologic scores, prostatic ultrasonographs and serum testosterone concentrations.(16) In the study, 20 dogs with BPH, determined by raised prostatic volume and prostatic volume per kilogram body weight, received saw palmetto extract (type of extract not specified) 1500 mg daily in meatballs (n = 8), 300 mg daily in meatballs (n = 6) or unmedicated meatballs (n = 6), for 91 days. Dogs included in this study did not have clinical signs of BPH (i.e. decreased urinary flow and residual urine volume) that often occur in human males with BPH. Dogs did not appear to be randomly assigned to treatment, and the mean prostatic volume in the control group was higher than that in the active treatment groups before treatment, although it was stated that this was not statistically significant. Assessments and data analysis were carried out by blinded investigators.

Spasmolytic activity and effects on the micturition reflex have also been documented for saw palmetto extract, although the contribution of these effects to effects in men with BPH is unclear. In anaesthetised, saline-infused rats, mean micturition interval, micturition volume and bladder capacity were significantly increased, and maximum micturition pressure was significantly decreased, compared with baseline values (p < 0.05 for each), in animals that received intraduodenal administration of saw palmetto extract (Permixon) at a dose of 60 mg/kg body weight, but not 6 mg/kg body weight.(17) In anaesthetised rats infused with 0.1% acetic acid, mean micturition interval, micturition volume and bladder capacity were significantly increased, compared with baseline values (p < 0.05 for each), in animals that received intraduodenal administration of saw palmetto extract (Permixon) at a dose of 12 or 20 mg/kg body weight. However, p values for statistical tests comparing saw palmetto-treated rats with vehicletreated rats (control group) are not reported for these sets of experiments. In rats given saw palmetto extract 6 mg/kg body weight orally for 14 days, total mean micturition volume was increased significantly, compared with baseline values, for days 9 to 14 (p < 0.05); however, a comparison with a parallel control group was not reported. Further experiments using rat bladder and prostate tissues showed that saw palmetto extract (10 to 300 mg/mL) competitively inhibited the binding of [N-methyl-3H]-

An ethanolic lipidic extract was reported to produce a concentration-dependent relaxation of rat uterus tonic contraction induced by vanadate (EC50 11.41 mg/mL).(18) Further

investigation suggested that a mechanism for the observed effect could be interference with intracellular calcium mobilisation, possibly mediated via cyclic AMP. Other in vitro studies demonstrated that a lipophilic ethanolic extract of saw palmetto 0.3–0.75 mg/mL reduced norepinephrine (noradrenaline)-induced contractions in rat deferential duct. Further study indicated that the relaxant effect of saw palmetto extract results from either a- adrenoceptor blockade or from calcium-blocking activity.(19)

(derived from human adenocarcinoma of the prostate) into Matrigel in vitro in a concentration-dependent manner at concentrations in the range 1–10 mg/mL.(24) However, LNCaP cells and SKRC-1 cells (derived from human renal carcinoma) were unaffected by the extract. The extract was also shown to inhibit the activity of urokinase-type plasminogen activator, a protease enzyme that is necessary for tumour-cell invasion into basement membranes. The monoacylglycerides 1-monolaurin and 1-monomyristicin isolated from saw palmetto demonstrated in vitro activity against renal (A-498) and pancreatic (PACA-2) human tumour cells (EC50 for 1-monolaurin: 3.77 mg/mL and 2.33 mg/mL, respectively; EC50 for 1-monomyristicin: 3.58 mg/mL and 1.87 mg/mL, respectively).(2) However, only borderline cytotoxicity was observed against PC-3 cells (EC50 for 1-monomyr- isticin: 8.84 mg/mL).(2)

PC-SPES, a combination preparation containing saw palmetto fruit extract and seven other herbal ingredients, has cytotoxic and

524 Saw Palmetto

pro-apoptotic activity in vitro in prostate carcinoma cells,(25) and in drug-sensitive (H69) and drug-resistant (H69V) human smallcell lung carcinoma cells.(26) Batches of PC-SPES have, however, been found to be adulterated with diethylstilbestrol, indometacin and/or warfarin, and cytotoxic activity in prostate carcinoma cells has been attributed to these contaminants.(25) In contrast, in experiments involving H69 and H69V cells, the cytotoxic activity of the contaminants was insufficient to account for the cytotoxicity of PC-SPES.(26) Adding contaminants to a 'less' contaminated batch of PC-SPES did not alter the cytotoxic activity of the herbal preparation in H69 and H69V cells. None of the contaminants displayed apoptotic activity at concentrations found as contaminants and higher, whereas both contaminated and 'less contaminated' batches of PC-SPES exhibited proapoptotic activity in these small-cell lung carcinoma cell lines.(25)

Other activities In vivo oestrogenic activity in the rat has also been documented for an alcoholic extract.(27) Activity was attributed to the high content of b-sitosterol, a known oestrogenic agent, present in saw palmetto.

In vivo anti-oedema activity in the rat has been documented for a hexane extract of saw palmetto, acting by inhibition of histamine-induced increase in capillary permeability.(28) Low doses of an aqueous extract were effective in carrageenan-induced paw oedema and pellet tests in the rat, although the extract was not found to influence the proliferative stage of inflammation.(1, 29) The observed anti-inflammatory activity was attributed to a high molecular weight polysaccharide (approximately 100 000). Polysaccharides possessing immunostimulating activity have also been documented for saw palmetto and were stated to contain a high content of glucuronic acid.(1, 29)

An extract (SG-291) prepared from saw palmetto fruits by supercritical fluid extraction with carbon dioxide was reported to inhibit both cyclooxygenase and 5-lipoxygenase in vitro (IC50 28.1 mg/mL and 18.0 mg/mL, respectively).(30) Further study indicated that the component(s) of saw palmetto extract that inhibits these enzymes must be within the acidic lipophilic fraction. Subsequent studies have documented that a liposterolic extract of saw palmetto (Permixon) significantly inhibited the production of 5-lipoxygenase metabolites, including leukotriene

B4, by human polymorphonuclear neutrophils at concentrations of saw palmetto extract of 5 mg/mL and above.(31)

SClinical studies

Pharmacokinetics Some data on the pharmacokinetics of saw palmetto extracts in healthy male volunteers (n = 12) come from an open, randomised, single-dose bioequivalence study of a 320mg capsule of a liposterolic extract of saw palmetto compared

with two capsules of saw palmetto extract 160 mg as the reference preparation.(32) The plasma concentration–time curves were reported to be almost identical for both preparations. The

maximum concentration (Cmax) for saw palmetto extract 320-mg capsule and 2 160-mg capsules was 2.54–2.61 mg/mL and 2.57–

2.67 mg/mL, respectively, and time to Cmax (Tmax) was 1.58 and 1.5 hours for the 320-mg capsule and 2 160-mg capsules,

respectively. Another study explored the bioavailability and

pharmacokinetic profile of a rectal formulation of saw palmetto extract 640 mg in healthy male volunteers (n = 12).(33) The mean

maximum plasma concentration of the second component of saw palmetto was almost 2.6 mg/mL at around three hours after drug administration.

Pharmacodynamics The inhibitory effects of saw palmetto extract on 5-a-reductase activity documented in vitro (see Pharmacological Actions, In vitro and animal studies) have been confirmed in some studies in humans, and refuted by others.

In one study, 25 men with symptomatic, established BPH were randomised to receive either a liposterolic extract of saw palmetto

(Permixon) 320 mg/day for three months (n = 10), or no treatment (n = 15).(34) At the end of the treatment period, analysis of

samples of BPH tissue, obtained by suprapubic prostatectomy, showed that dihydrotestosterone concentrations were significantly reduced and that testosterone concentrations were significantly higher in the treatment group, compared with the control group (p < 0.001 for both). A significant reduction in concentrations of epidermal growth factor in total BPH tissue was also observed in the treatment group, compared with the control group (p < 0.01). The reported biochemical effects were most evident in BPH tissue from the periurethral region.

In another study, biopsy specimens of the prostate were taken from 44 men with symptomatic BPH participating in a randomised, placebo-controlled trial of a herbal combination preparation containing saw palmetto lipoidal extract 106 mg together with nettle root extract, pumpkin seed oil, lemon bioflavonoid extract and vitamin A.(35, 36) There were no statistically significant differences in median tissue dihydrotestosterone and testosterone concentrations between the treatment and placebo groups at baseline. At the end of the study, mean tissue dihydrotestosterone concentrations decreased significantly in the treatment group, compared with baseline values (p = 0.005), whereas there was no significant change in dihydrotestosterone concentrations in the placebo group. However, in a separate analysis, it was reported that the median change in tissue dihydrotestosterone concentrations for the treatment group (1.38 ng/g) did not differ significantly from the corresponding change in the placebo group (0.87 ng/g). The findings of this study should be interpreted cautiously as it is possible there are other explanations for the observed effect.

Another randomised, double-blind trial involving 18 men with BPH compared saw palmetto extract (IDS-89; Strogen) 640 mg

three times daily (i.e. six times the normal dose) for three months with placebo.(37) This high dose of saw palmetto extract achieved

only a moderate decrease in 5-a-reductase activity.

An open, randomised, placebo-controlled study involving 32 healthy male volunteers compared the effects of a liposterolic extract of saw palmetto (Permixon) 80 mg twice daily for seven days with those of finasteride 5 mg daily for seven days on inhibition of 5-a-reductase activity.(38) Serum dihydrotestosterone concentrations were reported to decrease significantly with finasteride, compared with baseline values, but no significant changes were observed for the saw palmetto and placebo groups. Thus, this study did not support a mechanism of action for saw palmetto in BPH by inhibition of 5-a-reductase activity.

In addition, in a double-blind, placebo-controlled, four-way, crossover study in which 12 healthy male volunteers received three different saw palmetto extract preparations (Prostagutt uno, Prostess uno, Talso uno; 320 mg daily for eight days each, separated by wash-out phases of at least two weeks), none of the study medications showed signs of a1-adrenoceptor subtype occupancy as determined by a radioreceptor assay.(39)

Effects of saw palmetto fruit extract on certain cytokines have also been described. In an open, randomised, multicentre study, 30 men with BPH received a liposterolic extract of Serenoa repens (Permixon) 160 mg twice daily for three months before undergoing surgery, or to no treatment for three weeks before undergoing

surgery.(40) It was stated that at the end of the three-month treatment period, prostatic tissue concentrations of the cytokines TNF-a and interleukin-1b were significantly lower in Permixon recipients, compared with participants in the no-treatment control group (p = 0.012 and 0.004, respectively). No significant differences were observed, however, in concentrations of IL-6, TGF (transforming growth factor) or EGF (epidermal growth factor).

The effects of a combination preparation containing 106 mg of a lipoidal extract of saw palmetto, as well as nettle root extract, pumpkin seed oil, lemon bioflavonoid extract and vitamin A, were

assessed in a randomised, double-blind, placebo-controlled trial involving 40 men with symptomatic BPH.(41) At the end of the six-

month study, 23/60 and 25/60 nuclear morphometric descriptors (NMDs) for nuclei of 200 randomly selected epithelial cells were altered, compared with baseline characteristics, in prostatic tissue from men in the treatment group and placebo groups, respectively. A statistically significant multivariate change from baseline in NMDs was apparent for the treatment group but not the placebo group. These preliminary data may reflect effects such as alterations in gene expression, but this and the contribution of the saw palmetto extract, require testing in further studies.(41)

Therapeutic effects Numerous clinical studies have investigated the effects of saw palmetto extracts in men with BPH.

A systematic review and meta-analysis included 21 randomised

controlled clinical trials (18 of which were double-blind) of saw palmetto extracts involving a total of 3139 men with BPH.(42) This

work is an update of a previous Cochrane systematic review.(43) The updated review included 12 studies which compared saw palmetto extracts alone with placebo, four comparing saw palmetto extracts in combination with other herbals with placebo, two comparing saw palmetto extracts alone with an active control, one comparing saw palmetto extracts in combination with other herbals with an active control, one comparing saw palmetto extract with another herb and with placebo, and one comparing oral saw palmetto extract with a rectal formulation of saw palmetto extract. The mean duration of the included studies was 13 weeks (range 4–48 weeks).

Compared with placebo, saw palmetto extracts were associated with a decrease in urinary symptom scores (weighted mean difference (WMD), 95% confidence interval (CI): 1.41, 2.52 to0.30; one trial), nocturia (WMD, 95% CI: 0.76, 1.21 to0.32; ten trials) and residual volume (WMD, 95% CI: 22.95,42.33 to 3.56; six trials), and improvements in peak urine flow (WMD, 95% CI: 1.86, 0.60 to 3.12; nine trials), mean urine flow (WMD, 95% CI: 2.23, 1.18 to 3.27; four trials) and physician and self-rating of urinary symptoms (weighted risk ratio, 95% CI: 1.72, 1.11 to 2.66; three trials and 1.76, 1.21 to 2.54; six trials, respectively).(42) Saw palmetto extracts had no effect, however, on prostate size.

Compared with finasteride, saw palmetto extracts (monoand combination preparations) achieved similar improvements in urinary symptom scores, frequency of nocturia, peak urine flow, mean urine flow and residual volume, but not prostate size.

The conclusions of the review were that there is evidence that preparations containing saw palmetto improve urinary symptoms and flow measures in men with BPH and that improvement is similar to that achieved with finasteride. However, the review included trials which assessed the effects of preparations containing saw palmetto alone and in combination with other herbal ingredients, as well as saw palmetto preparations produced by different manufacturers, which vary qualitatively and quantita-

involving 132 men with BPH compared the effects of saw palmetto

526 Saw Palmetto

extract (Prostaserene) 320 mg once daily with 160 mg twice daily for one year.(50) Another study compared a liposterolic extract of

saw palmetto (Permixon) 320 mg daily with 160 mg twice daily for three months in 100 men with symptomatic BPH.(51) For each

regimen, both studies reported significant improvements in the mean IPSS, maximum and mean urinary flow rates and residual urine volume, at the end of the studies, compared with baseline values. However, as these studies did not include a placebo-control group, the possibility that the observed effects are placebo effects cannot be excluded.

Several open, uncontrolled studies of saw palmetto extracts (alone or in combination with other herbs), several of which were drug-monitoring studies which also assessed effectiveness, have reported improvements in symptoms of BPH at the end of treatment, compared with baseline values.(52–56) Doses assessed in these studies were usually 160 mg two or three times daily for up to three years. These studies are discussed in more detail later (see Side-effects, Toxicity).

A small number of studies have explored the effects of saw palmetto extracts in disorders other than BPH. In a single-blind, controlled trial, 64 men with USA National Institutues of Health category III prostatitis (chronic pelvic pain syndrome) were randomised to receive saw palmetto extract 325 mg daily (not further specified), or finasteride 5 mg daily, for one year.(57) At the end of the study, the proportion of participants with a statistically significant improvement in Chronic Prostatitis Symptom Index score was higher for finasteride, compared with placebo (65% versus 24%; p < 0.02).

The effects of a softgel capsule preparation containing saw palmetto extract 200 mg (standardised for 85–95% liposterolic content) and b-sitosterol 50 mg in the treatment of androgenetic alopecia (which affects men and women) were assessed in a randomised, double-blind, placebo-controlled pilot trial.(58) In the study, 26 men aged 23 to 64 years with mild-to-moderate androgenetic alopecia received one softgel capsule, or placebo, twice daily for up to 21 weeks (precise duration of treatment not stated). Overall, 19 men completed the study and, for these, investigator-assessed hair growth was deemed to be improved in a greater proportion of those who received the active treatment, compared with those who received placebo (60% versus 11%), although no statistical tests were undertaken. With respect to participants' self-assessment of their hair condition, none of the active treatment recipients thought their condition had deteriorated, compared with 33% of placebo recipients. The hypothesis

Sthat saw palmetto extract (with b-sitosterol) is beneficial in androgenetic alopecia requires testing in well-designed randomised controlled trials.

Saw palmetto is one of the eight herbal ingredients contained in a commercial preparation known as PC-SPES; the other herbal ingredients were stated as being chrysanthemum, isatis, licorice,

Ganoderma lucidum, Panax pseudoginseng, Rabdosia rubescens and Scutellaria (scullcap). The combination preparation has been

investigated for oestrogenic activity, and for its potential effects in the treatment of hormone-sensitive prostate cancer.(59) In a randomised, controlled, crossover trial, 90 men with androgenindependent prostate cancer received three capsules of PC-SPES three times daily, or diethylstilbestrol 3 mg once daily. Participants crossed to the other arm of the study on reaching clinical or prostate-specific antigen progression. The median times to

progression for PC-SPES and diethylstilboestrol were 5.5 and 2.9 months, respectively.(60) However, the study was terminated prematurely because PC-SPES was withdrawn from the market after being found to be contaminated with diethylstilbesterol and

ethinylestradiol. Other contaminants, including warfarin and indometacin have also been reported.(25, 26)

Side-effects, Toxicity

Clinical data

A systematic review and meta-analysis included 21 randomised controlled clinical trials (18 of which were double-blind) of saw palmetto extracts involving a total of 3139 men with BPH (see Clinical studies, Therapeutic effects).(42) Of these,12 studies compared saw palmetto extracts alone with placebo; the mean duration of all included studies was 13 weeks (range 4–48 weeks). The review found that the frequency and type of adverse events reported for saw palmetto extracts were similar to those reported for placebo. There were no statistically significant differences between participant withdrawal rates for saw palmetto, placebo and finasteride (8.9, 7.1 and 9.0%, respectively; p = 0.17 for saw palmetto versus placebo and p = 1.0 for saw palmetto versus finasteride), and in the frequency of gastrointestinal adverse events (1.3, 0.9, 1.5%, respectively; p > 0.5 for saw palmetto versus finasteride). Impotence was reported more frequently by finasteride recipients than by saw palmetto recipients, or placebo recipients (4.9, 1.1 and 0.7%, respectively; p < 0.001 for saw palmetto versus finasteride and p= 0.58 for saw palmetto versus placebo).(42) Clinical trials, however, are designed primarily to assess efficacy, not safety, and have the statistical power only to detect common acute adverse effects.

Several post-marketing surveillance type studies involving over 4000 men with BPH have assessed the safety and tolerability of different saw palmetto extracts taken at recommended doses and have also found preparations to be well-tolerated. Studies conducted to date have, however, assessed the effects of several different preparations of saw palmetto extract; these are likely to vary qualitatively and quantitatively in their pharmaceutical quality, and the implications of this for safety of specific products should be considered. Some studies have monitored the effects of longer term treatment (one to three years) with saw palmetto preparations, but further well-designed post-marketing surveillance studies are necessary to assess the safety of use of saw palmetto fruit extracts in men with BPH for even longer periods. To date, almost all clinical studies of saw palmetto fruit products have involved men only, so there is a lack of information on the safety of saw palmetto fruit preparations when used by women (for example, for androgenetic alopecia and other conditions such as acne).

In a drug-monitoring study involving 1334 men with BPH, the tolerability of saw palmetto extract 160 mg twice daily for 12 weeks was reported to be 'good' or 'excellent' by more than 95% of participants.(55) This is similar to a finding from a three-year prospective, uncontrolled study involving 435 men with BPH, in which the tolerability of saw palmetto extract (IDS-89) 160 mg twice daily was classified as 'good' or 'very good' by both physicians and patients for 98% of participants.(54) A total of 46 adverse events was reported in 34 patients. Of these, 30% were gastrointestinal disturbances. The withdrawal rate from the study was 1.8%, mostly because of digestive disturbances (n = 3) and tumours (n = 3). Non-serious adverse effects (4.95–6.63%), mainly minor gastrointestinal effects, such as gastralgia, nausea, diarrhoea, constipation and anorexia, as well as vertigo, headache, dry mouth and pruritus, were reported in an open study involving 413 men with BPH who received saw palmetto extract 160 mg twice daily for three months.(53) An observational study involving

2080 patients with BPH who received a combination of saw palmetto extract (WS-1473) and nettle root extract (WS-1031) reported that the tolerability of the preparation was classified by physicians to be 'good' or 'very good' for the majority of participants.(56) Mild adverse effects were reported in 15 patients (0.72%).

Studies assessing the equivalence of two different regimens of saw palmetto extract (320 mg once daily and 160 mg twice daily)

report that adverse events occurred with a similar frequency in both groups.(50, 51) Most events were deemed to be unrelated or

unlikely to be related to treatment with saw palmetto extract. In a small obervational study involving 155 men with BPH who

received a lipidosterolic extract of saw palmetto (Permixon) 160 mg twice daily for two years, 10 adverse events (including four cardiovascular events; not further specified), none of which were considered to be related to saw palmetto, were reported by nine participants (5.8%).(61) However, the study did not involve sufficient numbers of participants to have the statistical power to detect rare adverse effects.

An isolated report describes a 53-year-old white man with a

meningioma who experienced a bleeding episode during resection of the tumour.(62) The man lost around two litres of blood before

the haemorrhage was stopped using standard treatments. Laboratory values for prothrombin time and activated partial thromboplastin time were reported to be within normal ranges, although the bleeding time when measured after surgery was found to be 21 minutes (normal range reported to be 2–10 minutes). The bleeding normalised over the next five days. The patient stated that he had not taken non-steroidal antiinflammatory agents before undergoing surgery, but said he had been taking saw palmetto for BPH. The authors of the report stated that the prolonged bleeding time was 'probably' due to cyclooxygenase inhibition caused by saw palmetto and affecting platelets. However, this case relies on the patient's self-report of saw palmetto use, no details of the saw palmetto product implicated were provided in a report of the case, and no analysis of the product was undertaken. Causality has not been established.

The World Health Organization's Uppsala Monitoring Centre (WHO-UMC; Collaborating Centre for International Drug Monitoring) receives summary reports of suspected adverse drug reactions from national pharmacovigilance centres of over 70 countries worldwide. To the end of the year 2005, the WHOUMC's Vigisearch database contained a total of 187 reports, describing a total of 313 adverse reactions, for products reported to contain S. repens only as the active ingredient (see Table 1).(63) This number may include the case reports described above. Reports originated from several different countries.

Toxicity Incubation of high concentrations of saw palmetto extract (Permixon) 9.0 mg/mL for 48 hours inhibited sperm motility, compared with control.(64) Cytotoxic activity has been described for saw palmetto fruit extracts and certain individual constituents in vitro (see Pharmacological Actions, In vitro and animal studies).

Contra-indications, Warnings

None specified. BPH, the main intended use for saw palmetto, is not suitable for self-treatment.

Drug interactions In view of the reported anti-androgen and oestrogenic activities, the possibility that saw palmetto extracts could affect concurrent hormonal therapy, including the oral

contraceptive pill and hormone replacement therapy, should be considered. Drug interaction studies involving small numbers of healthy volunteers who received saw palmetto extracts have indicated that 14 or 28 days' oral administration of saw palmetto

extract 320 mg daily (equivalent to 396 mg non-esterified fatty acids and 6.3 mg b-sitosterol daily,(65) or 277 mg non-esterified

fatty acids daily(66)) did not influence the activity of the cytochrome P450 enzymes CYP2D6, and CYP 3A4,(65, 66) and also CYP1A2 and CYP2E1.(66)

Table 1 Summary of spontaneous reports (n = 187) of suspected adverse drug reactions associated with single-ingredient Serenoa repens preparations held in the Vigisearch database of the World

Health Organization’s Uppsala Monitoring Centre for the period up to end of 2005(63, a, b)

aSpecific reactions described where n = 3 or more

bCaveat statement. These data were obtained from the Vigisearch database held by the WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden. The information is not homogeneous at least with respect to origin or likelihood that the pharmaceutical product caused the adverse reaction. Any information included in this report does not represent the opinion of the World Health Organization

528 Saw Palmetto

Pregnancy and lactation The safety of saw palmetto has not been established. In view of the lack of toxicity data and the documented hormonal activity, the use of saw palmetto during pregnancy and lactation should be avoided.

Preparations

Proprietary single-ingredient preparations

Argentina: Beltrax Uno; Permicaps; Permixon. Australia: Bioglan Pro-Guard; Prosta. Austria: Permixon; ProstaUrgenin. Belgium: Prosta-Urgenin; Prostaserene. Brazil: Prostalium; Prostatal; Renopen. Chile: Prostafort. Czech Republic: Capistan; Prostakan Mono; Prostamol Uno. Denmark: Spalda Sabal. France: Permixon. Germany: Azuprostat Sabal; Evipro- stat-S; Hyperprost Uno; Normurol; Planturol; Prosta-Urgenin; Prosta Urgenin Uno; Prostagutt mono; Prostagutt uno; Prostaplant; Prostess; Remiprostan uno; Sabacur uno; Sabal; Sabal uno; Sabalvit; Sabonal Uno; Sita; Steiprostat; Strogen; Talso. Greece: Libeprosta. Hungary: Prostakan; Prostamol Uno; Strogen Uno. Israel: Permixon. Italy: Permixon; Prosteren; Rilaprost; Saba; Serpens. Mexico: Permixon; Prostasan; Prostex; Urogutt. Portugal: Permixon; Prostiva. Russia: Permixon (Пермиксон); Prostamol Uno (Простамол Уно). Spain: Permixon; Sereprostat. Switzerland: Permixon; Prosta-Urgen- ine; ProstaMed; Prostasan; SabCaps. Thailand: Permixon. UK: Sabalin; Sabalin. Venezuela: Permixon.

Proprietary multi-ingredient preparations

Argentina: Anastim con RTH; Argeal; Catiz Plus; Keracnyl; Keracnyl; Normoprost Plus; PR21; Sabal; Ultracal. Australia: Bioglan Mens Super Soy/Clover; Extralife Flow-Care; Lifechange Mens Complex with Saw Palmetto; Serenoa Complex; Urapro; Urgenin; Urinase. Austria: Prostagutt; SpasmoUrgenin; Urgenin. Belgium: Urgenin. Canada: DamianaSarsaparilla Formula; Prostate Ease; Prostease; ProstGard. Czech Republic: Prostakan Forte. France: Argeal; Kelual DS; Keracnyl; Keracnyl; Sabal. Germany: Cefasabal; Granu Fink Prosta; Nephroselect M; Prostagutt forte. Hong Kong: PhytoEase; Prostease; Urgenin. Israel: Urgenin. Italy: Biothymus M Urto; Prostaplant. Malaysia: Total Man. Mexico: Prosgutt. Portugal: Efluvium Anti-caspa; Efluvium Anti-seborreico; Spasmo-Urgenin. Singapore: Palmetto Plus. Spain: Neo Urgenin; Spasmo-Urgenin; Urgenin. Switzerland: Granu Fink

S Prosta; Prosta-Caps Chassot N; Prostagutt-F. Thailand: Spasmo-Urgenin. UK: Antiglan; Daily Fatigue Relief; Damiana and Kola Tablets; Elixir Damiana and Saw Palmetto; Prostaid; Regina Royal Concorde; Roberts Black Willow Compound Tablets; Strength; Strength Tablets; Supa-Tonic Tablets. USA: ProstatExcell; Prostate Health.

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