An open label, randomized, fixed-dose, crossover study comparing efficacy and safety of sildenafil citrate and saffron (Crocus sativus Linn.) for treating erectile dysfunction in men naïve to treatment

Abstract

Saffron (Crocus sativus Linn.) have been perceived by the public as a strong aphrodisiac herbal product. However, studies addressing the potential beneficial effects of saffron on erectile function (EF) in men with ED are lacking. Our aim was to evaluate the efficacy and safety of saffron administration on EF in men with ED. After a 4-week baseline assessment, 346 men with ED (mean age 46.6±8.4 years) were randomized to receive on-demand sildenafil for 12 weeks followed by 30 mg saffron twice daily for another 12 weeks or vice versa, separated by a 2-week washout period. To determine the type of ED, penile color duplex Doppler ultrasonography before and after intracavernosal injection with 20 μg prostaglandin E1, pudendal nerve conduction tests and impaired sensory-evoked potential studies were performed. Subjects were assessed with an International Index of Erectile Function (IIEF) questionnaire, Sexual Encounter Profile (SEP) diary questions, patient and partner versions of the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire and the Global Efficacy Question (GEQ) ‘Has the medication you have been taking improved your erections?’ No significant improvements were observed with regard to the IIEF sexual function domains, SEP questions and EDITS scores with saffron administration. The mean changes from baseline values in IIEF-EF domain were +87.6% and +9.8% in sildenafil and placebo groups, respectively (P=0.08). We did not observe any improvement in 15 individual IIEF questions in patients while taking saffron. Treatment satisfaction as assessed by partner versions of EDITS was found to be very low in saffron patients (72.4 vs 25.4, P=0.001). Mean per patient ‘yes’ responses to GEQ was 91.2 and 4.2% for sildenafil and saffron, respectively (P=0.0001). These findings do not support a beneficial effect of saffron administration in men with ED.

Introduction

The National Institutes of Health defined medically ED as ‘a continuous or repetitive inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse’.1 The 1988 advent of phosphodiesterase type 5 inhibitor (Viagra) medicalized ED treatment and enabled men to seek out medical helps to their sexual disorders. This medicalization of impotence2 has profoundly affected the type of treatments being offered for impaired erectile function (EF). In our community, considerable numbers of men who experience decreased EF tend to avoid medical treatment, believing that ED drugs are not for them due to a variety of reasons. Traditional or alternative medicine still has a significant role in the lives of many people. There is anecdotal evidence, which demonstrates that most men are asking physicians about alternative treatments such as herbal remedies and nutritional supplements for diminished EF.3 The popularity of herbal remedies is increasing all over the world because of the general belief that natural products are safer and healthier than synthetic medications. Compared with the enormous literature on pharmaceutical treatments of ED, very few studies have addressed the efficacy of herbal remedies known as ‘aphrodisiacs’. In our community, several plants are used as ‘aphrodisiacs’, the most famous of them is saffron (Crocus sativus Linn.).

Saffron is a perennial stemless herb of the Iridaceae family. It is highly valued as a food spice for its flavoring and coloring properties,4 as it also gives taste and aroma. Saffron as condiment spice is made up of the dried stigmas of C. sativus L., which is cultivated in few countries. Although worldwide total annual production of saffron is about 190 tons, Iran produces about 90% of the total.5, 6 The main active ingredients in saffron are glucosyl esters of crocetin ((8,8′-diapocarotene-8,8′-dioic acid; C20H24O4), water-soluble glycosidic cis- and trans-carotenoids crocins, both accountable for its coloring property), picrocrocin (C16H26O7) for the bitter taste and safranal (C10H14O) for the aroma.7, 8 Interest in the impact of saffron on human health is raising due to their high antioxidant properties,9, 10 and its pharmacological activities such as treatment of memory impairment, anticatarrhal, antidepressant, carminative, anticonvulsant, antispasmodic, emmenagogue, and especially for their antitumor effect.4, 11 In traditional medicine, saffron is suggested also as aphrodisiac herbal remedy.12 The aphrodisiac properties of C. sativus stigma aqueous extract and its constituent crocin have been shown in previous studies.13, 14 In a pilot study by Shamsa et al.,14 20 men with ED have been treated with 200 mg saffron daily. After 10 days, saffron exerted positive effect on EF.

To date there have been no published studies in the available literature comparing sildenafil and saffron. There are certain problems inherent in comparing two medicinals with different methods of action and, more importantly, different methods of administration. Although the ideal study might have been a randomized, double-blind, placebo-controlled, crossover trial, mainly for pragmatic and ethical reasons we performed an open-label, randomized, fixed-dose, crossover study to compare the efficacy and safety of the two medications.

Materials and methods

Study population

A total of 378 men with ED who were referred or addressed themselves to our sexual dysfunction clinic between January 2007 and May 2009 were enrolled in this study.

Eligible patients were those between 18 and 60 years of age, who had a minimum 6-month history of ED, were in a stable sexual relationship for 6 months, and had never received any treatment for ED.

The mean age of the patients was 46.6±8.4 (range, 27–60) years, and the mean duration of ED was 18.8±6.9 (range, 6–28) months. After study requirements and possible side effects were explained to patients, all the subjects gave their informed consent before entering the study. The study protocol was approved by the local Medical Ethics Committee and conformed to the ethical guidelines of the 2002 Declaration of Helsinki.

Evaluations

All subjects were seen with their partners and interviewed separately about sexual activity and patient EF. The first visit included a detailed sexual, medical and surgical history; physical examination; status of current diseases; and concomitant medication. The etiology of ED was determined by medical history, penile color duplex Doppler ultrasonography before and after intracavernosal injection with 20 μg prostaglandin E1, pudendal nerve conduction tests, impaired sensory-evoked potential studies, and a nocturnal penile tumescence test using RigiScan-Plus device (Timm Medical Technologies, Inc, Eden Prairie, MN, USA). Routine laboratory analyses were complete blood count, urinalysis, blood chemistry, serum lipid profile, and serum values of following hormones: luteinizing hormone, follicle-stimulating hormone, thyroid stimulating hormone, testosterone and prolactin.

Inclusion criteria

At the baseline visit, participants were screened for eligibility; the primary inclusion criteria were a minimum age of 18 years, a diagnosis of non-endocrinological ED according to the National Institutes of Health statement on ED,1 naïve to treatment for ED, a stable heterosexual relationship for at least the previous 6 months, and a steady relationship with the same female partner.

Exclusion criteria

Men were excluded from the study if they had a history of hypotension (blood pressure 90/50 mm Hg or less) or hypertension (blood pressure 160/100 mm Hg); retinitis pigmentosa, significant cardiovascular disease, pelvic surgery, stroke or spinal cord injury; neurological and psychiatric disorder; impaired hepatic and renal function or history of cancer; were receiving treatment with nitrates, hormones or psychotropic and antidepressant medication; had a history of drug or alcohol abuse; did not have a sexual partner; and were affected by another sexual disorder such as premature ejaculation. Patients with endocrinological cause of ED, already being treated for ED, clinically significant penile deformity, any endocrinopathy such as thyroid disease, uncontrolled diabetes mellitus (Hb A1c>7), psychiatric or neurological disease, and relationship problems were also excluded.

Other exclusion criteria were current treatment with nitrites, androgens, antiandrogens or cancer chemotherapy; and concurrent use of potent cytochrome P450 3A4 inhibitors (that is, ritonavir).

Patients were asked to attempt sexual intercourse at least once per week during the study; if they did not, they would not be permitted to continue with the trial.

Of the initial 378 recruited patients, 346 met study requirements and consented to continue with study protocol.

Plant material

The dried saffron (C. sativus L.) stigma was purchased from Novin Saffron Co, Mashhad, Iran.

The stigma extract was prepared using the procedure as described by Akhondzadeh et al.15 In brief, 120 g of dried and milled petal of C. sativus L. was extracted with 1800 ml ethanol (80%) in three steps using percolation method. Then the production of ethanol extract was dried at temperature between 35 and 40 °C by evaporation procedure. The final production was formulated as capsule. The active ingredients of each capsule were C. sativus (15 mg), sodium starch glycolate as disintegrant, lactose as filler and magnesium stearate as lubricant.

Treatment protocol

The study consisted of a 4-week baseline screening period and two 12-week treatment periods separated by a 2-week washout period. First, patients were randomly assigned in each initial treatment arm; 173 patients started on on-demand sildenafil (50 mg) and another 173 on saffron (30 mg) twice daily for 12 weeks. Following the first treatment period, after a 2-week medication washout phase, patients were crossed over to the alternative treatment for the second 12-week treatment period (Figure 1). The sequence of the two treatments was established by a randomization list in blocks in closed packets. Patients were instructed to take sildenafil 1 h before planned sexual activity and 2–3 h after a low-fat meal. The absolute need for sexual stimulation, such as visual stimulation, foreplay and hugging, was also emphasized. The men were told that the recommended starting dose of sildenafil was 50 mg. They were instructed to rapidly increase the dose from 50 to 100 mg after one attempt if the initial treatment was not satisfactory and there were no adverse events. The maximum allowed dosing frequency was once per day. All the participants received the standard instruction sheet inserts for each medication.

Figure 1
figure1

The study design.

The men were asked not to use any other form of ED treatment for the whole duration of the study.

Patients were given a sexual-encounter diary in which to record the date and time of each sexual attempt. Diaries and unused study medications were collected at the end of each 12-week treatment period. Crossover study design was chose to define whether the treatment with saffron was effective, with respect to sildenafil, for each patient.

Each patient's participation was voluntary and was given the opportunity to withdraw at any time he desired.

Outcome measures

All patients were assessed for 1 week before being treated and every 2-week during each treatment arm by the investigator. At each follow-up visit, a physical examination were performed, as well as 12-lead electrocardiography, additional safety evaluations, including measurements of serum aspartate aminotransferase, alanine aminotransferase, lactic dehydrogenase, alkaline phosphatase and fasting blood sugar, and a complete blood count with differential.

The primary end points included a comparison of the efficacy of sildenafil and saffron using the (1) responses to questions 3 (ability to achieve an erection) and 4 (ability to maintain an erection) on the International Index of Erectile Function (IIEF);16 (2) IIEF based on the score for the five separate response domains; (3) and the mean per-patient percentage of ‘yes’ responses to Sexual Encounter Profile (SEP) questions.

The IIEF is a validated, multidimensional, self-administered questionnaire of 15 questions that specifically address all the five aspects of male sexual function, including EF questions 1–5 and 15 (score range 1–30), orgasmic function questions 9 and 10 (score range 0–10), sexual desire questions 11 and 12 (score range 2–10), intercourse satisfaction questions 6 through 8 (score range 0–15), and overall satisfaction questions 13 and 14 (score range 2–10). Using the five-category severity classification system of Cappelleri et al.,17 ED severity can be categorized into five distinct domain according to total IIEF-EF domain score: no ED (score of 26–30), mild ED (score of 22–25), mild-to-moderate ED (score of 17–21), moderate ED (score of 11–16) and severe ED (score, 6–10). For the purpose of this study, the severity of ED was classified into three separate groups: mild ED (score of 17–25), moderate ED (score of 11–16) and severe ED (score of 1–10).17

SEP questions were the following: SEP1 ‘Were you able to achieve at least some erection (some enlargement of the penis)?’; SEP2 ‘Were you able to insert your penis into your partner's vagina?’; SEP3 ‘Did your erection last long enough for you to have successful intercourse?’; SEP4 ‘Were you satisfied with the hardness of your erection?’; and SEP5 ‘Were you satisfied overall with this sexual encounter?’

The secondary outcome measures were: (1) patient and partner versions of the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire; (2) the Global Efficacy Question (GEQ) ‘Has the medication you have been taking improve your erections?’; and (3) weekly sexual intercourse.

EDITS is a validated questionnaire for assessing patient and partner satisfaction to ED treatment.18 The EDITS index is calculated by multiplying the mean EDITS score by 25, resulting in a treatment satisfaction range of 0, extremely dissatisfied to 100, extremely satisfied. The EDITS index is further dichotomized as satisfied (index >50) vs unsatisfied (index 50).18

Safety assessment

Patient-reported treatment-emergent adverse events (TEAEs) were defined as events that first occurred or became worse after taking the first dose of study medication. In addition, serious adverse event was defined as any adverse event requiring hospitalization, was life threatening, and resulted in death or persistent or significant disability or incapacity. The severity and relation to study drug of TEAEs were recorded using preferred terms in the Medical Dictionary for Regulatory Activities (MedDRA) version 7.0 (MedDRA MSSO, Reston, VA, USA).

Statistical analysis

A 298 patient sample size was estimated to be sufficient to provide 85% power to detect a 10% difference in IIEF-EF domain score between the saffron (estimated to be 20%) and sildenafil (estimated to be 75%) groups. To allow for 15% of patients not completing study after randomization, a minimum sample size of 352 would be required. The intention-to-treat principal was applied for all efficacy measures and included all subjects who had a baseline evaluation and had at least one efficacy assessment after the baseline visit. For subjects who discontinued early and missing data, the last observation carried forward was used. The analysis of safety was performed on all randomized subjects who took at least one dose of study medication. All statistical tests were performed at the two-sided 5% level of significance using Statistical Package for Social Sciences for Windows, version 16.0, software (SPSS, Chicago, IL, USA). Changes from baseline to end point were analyzed using a repeated measures analysis of variance model for a crossover design, including fixed terms for baseline score, treatment group and a random term for patient. No carryover effect was constructed, as 2 weeks of washout between treatment periods was considered sufficient to eliminate the pharmacodynamic properties of either saffron or sildenafil.

Efficacy analyses included the 15 individual IIEF questions, the IIEF domains, and SEP and EDITS questions, using similar crossover analysis of variance models as described above. An analysis of covariance model was also used to analyze the end of treatment (EOT) GEQ scores. Correlations among all domains of the IIEF were determined using Pearson's correlation coefficients.

Results

Patient disposition

Figure 2 shows the patient disposition; 378 men with ED assessed for eligibility, but 26 men failed the study inclusion/exclusion criteria, and another 6 were excluded after withdrawal of consent. In all, 346 patients were randomized, of whom 173 received sildenafil then saffron and 173 saffron then sildenafil. In all, 307 evaluable men completed the whole study protocol; reasons for discontinuation from the study are shown in Figure 2. The demographic and clinical characteristics of the study population are demonstrated in Table 1. Formal statistical analysis did not show obvious differences between the groups. Most men (74%) had ED for 1 year. At baseline, the ED severity was moderate or severe in 87% of the patients and the cause of ED was vasculogenic, neurogenic and psychogenic in 72.2, 3.5 and 24.3% of participants, respectively.

Figure 2
figure2

Study flow chart. EOT, end of trial.

Table 1 The baseline demographic and clinical characteristics

Efficacy assessment

Comparing the two treatment sequences demonstrated that there was no carryover effect in the trial.

Primary efficacy variables

Table 2 shows the mean end point and change from baseline to end point for the five sexual function domains of the IIEF questionnaire and fifteen individual IIEF questions. For the IIEF-EF domain, the mean change from baseline to end point after sildenafil (10.6) was higher than that of saffron (1.4) (P=0.001). The mean changes were also higher for the IIEF orgasmic function domain (1.9 vs 0.2, P=0.001), sexual desire (0.9 vs −0.4, P=0.01), intercourse satisfaction domain (4.8 vs −0.3, P=0.001) and overall satisfaction domain (3.1 vs −0.4, P=0.0001), although sexual desire was improved to a much lesser extent than the other domains (Table 2). Indeed, intercourse and overall satisfaction domains deteriorated during the use of saffron in comparison with baseline (−0.3 and −0.4%, respectively). We also checked the responses to questions 3 and 4 of the IIEF questionnaire to determine treatment efficacy. On each question, the improvement from baseline was statistically significant only after sildenafil administration. For question 3, the mean score before and after saffron was 2.5±0.2 and 2.4±0.2 (P=not significant), and the mean score before and after sildenafil was 2.4±0.2 and 4.2±1.2 (P=0.001), respectively. For question 4, the mean score before and after saffron was 2.1±0.2 and 2.0±0.2 (P=not significant), and the mean score before and after sildenafil was 2.0±0.2 and 3.9±1.3 (P=0.001), respectively. For the remaining 13 individual IIEF questions, the mean changes from baseline to end point were higher after sildenafil compared with saffron (Table 2).

Table 2 The IIEF domain and individual question score

The improvement in the mean per patient percentage ‘yes’ responses to the SEP diary questions was statistically significant only after sildenafil administration. The mean number of sexual attempts per patient was 44.6±6.6 with sildenafil and 39.2±4.3 for saffron (P=0.02). The total number of sexual attempts was 13 948 and 12 363 in the sildenafil and saffron groups, respectively (P=0.01). The percentage of attempts resulting in erection firm enough for successful penetration (SEP2) was significantly higher with sildenafil than with saffron (82.4 vs 42.4%, P=0.001) (Table 3). Saffron was not statistically superior over baseline. The proportion of attempts resulting in successful intercourse (SEP3) also demonstrated the statistical superiority of sildenafil over saffron (74.1 vs 21.6%) (P=0.0001). The statistical superiority of saffron over baseline was not demonstrated (P=0.1). For SEP1 (some erection) (87.5 vs 61.4%), SEP4 (satisfaction with hardness) (67.4 vs 8.4%) and SEP5 (overall satisfaction) (62.5 vs 6.6%), the mean changes from baseline were also significantly higher when men took sildenafil compared with saffron (all P 0.001).

Table 3 The mean per patient percentage of ‘Yes’ responses to the SEP diary questions

Secondary efficacy variables

Evaluation of the patients on sildenafil and saffron showed statistical difference in total patient and partner EDITS scores (Table 4). The total patient EDITS score was significantly higher in men who took sildenafil (78.6±12.6) than in those on saffron (27.4±4.5) (P=0.001). The total partner EDITS score was also significantly higher in patients who took sildenafil (72.4±12.4) than in those on saffron (25.4±3.6) (P=0.001). Furthermore, patients who took sildenafil had significantly higher mean scores on 11 individual EDITS items than did those who took saffron (P=0.001) (Table 4). Similarly, sildenafil-treated patients had significantly higher mean scores on the partner version of EDITS than saffron-treated patients with respect to five items: overall satisfaction, expectations, sexual desirability, how long the treatment lasts, and the patient's feeling about continuing treatment (all P0.01) (Table 4). Evaluation of the response to question 1 of the EDITS questionnaire, which determines overall satisfaction with treatment, revealed that a significantly higher number of patients who took sildenafil had a response of 3 or 4 (moderately or completely satisfied) than those on saffron (mean score, 3.1±0.2 vs 1.1±0.1; P=0.001). A significantly higher number of patients who took sildenafil responded to question 2 of the EDITS questionnaire, which assesses whether treatment met their expectations, with a response of 3 or 4 (considerably and completely) than those on saffron (mean score, 2.9±0.2 vs 0.9±0.1; P=0.001).

Table 4 Erectile Dysfunction Inventory for Treatment Satisfaction (EDITS) Index

The proportions of men answering ‘yes’ to GEQ for sildenafil and saffron was 91.2 and 4.2%, respectively (P=0.0001). At baseline, there was a mean of 1.2±0.1 and 1.2±0.2 (P=0.1) coitus episodes weekly in sildenafil and saffron groups, respectively. At the end of trial (EOT), sildenafil patients reported a significantly higher number of coitus episodes weekly compared with saffron patients (1.9±0.2 vs 1.5±0.2; P=0.01). Indeed, sildenafil was highly superior to saffron according to all the measurable end points.

Secondary analysis

There was a weak but significant correlation between the degree of ED and response to sildenafil (r=0.34, P=0.01). Even patients with severe ED had a 39% successful intercourse rate. Etiology of ED had a significant impact on positive response rate, with neurogenic causes of ED having significantly lower rates than psychogenic or vasculogenic ED. The success rate was 84% for patients with vasculogenic ED (r=0.64, P=0.001), 45% for patients with neurogenic ED (r=−0.65, P=0.001) and 63% for patients with psychogenic ED (r=−0.46, P=0.01). Owing to the very small response rate in subjects who were taking saffron, Pearson's correlation analysis between response rates to saffron and baseline ED severity and ED etiology was not possible in this study.

With sildenafil and saffron, mean IIEF-EF score increased to 87.6 and 11.5%, respectively (P=0.001) (Figure 3). This significant difference was also evident in other four IIEF domains, namely, orgasmic function domain (35.5 vs 3.5%; P=0.001), sexual desire domain (14.3 vs −6.3%; P=0.01), intercourse (71.6 vs −4.4%; P=0.001) and overall satisfaction domains (70.5 vs −8.8%; P=0.001).

Figure 3
figure3

The percentage change from baseline in IIEF domains. EFD, erectile function domain; ISD, intercourse satisfaction domain; OFD, orgasmic function domain; OSD, overall satisfaction domain; SDD, sexual desire domain.

As a percentage of the maximum mean IIEF questions 3 and 4 scores, there was a highly significant treatment effect for sildenafil compared with saffron (P=0.0001) for both question 3 (75 vs 8%) and question 4 (95 vs −4.8%) at EOT (Figure 4).

Figure 4
figure4

The percentage change from baseline in individual IIEF questions.

The greatest increase in mean per patient percentage of ‘yes’ responses to the SEP diary questions was noted for overall satisfaction item (SEP5) (878 vs −4.3%; P=0.0001), followed by intercourse satisfaction (SEP4) (764 vs 6.3%; P=0.0001) and successful intercourse (SEP3) (276 vs 14.3%; P=0.0001) (Figure 5).

Figure 5
figure5

The percentage change from baseline in SEP diary questions.

Of 307 men completing both treatment periods, 291 (94.8%) preferred sildenafil and 16 (5.2%) preferred saffron for ED therapy at the end of trial (EOT). The choice of medication was not significantly affected by patient age, ED severity, ED etiology and treatment sequence (that is, sildenafil followed by saffron or vice versa).

Adverse events

The adverse events profiles of the two medications were largely as might be expected from the published clinical trials and are shown in Table 5. Adverse effects related to treatment were noted in 20.8% (36 of 173) of patients taking sildenafil and 4.0% (7 of 173) of patients taking saffron (P<0.001). Of the patients taking sildenafil, 9.8% reported headache as an adverse event vs 2.9% of patients taking saffron; 8.1% taking sildenafil reported flushing vs 2.3% taking saffron; 4% taking sildenafil reported dyspepsia vs 1.7% taking saffron; and 4% taking sildenafil reported nasal congestion vs 0% taking saffron. Most adverse events were mild to moderate in nature. Seven patients in the sildenafil group permanently discontinued because of adverse events. The adverse events that resulted discontinuation were severe headache in three patients, moderate hot flushes with mild chest tightness in two, severe nasal congestion in one and nausea with dyspepsia in one. There were no serious adverse events with both medications. However, adverse effects on laboratory parameters and vital signs were noted in patients while they were taking saffron. Mean blood pressure (BP) at baseline in sildenafil and saffron groups was 124/72±8/6mm Hg and 126/72±8/6 mm Hg, respectively. During treatment with sildenafil and saffron, the mean BP was 126/72±7/6 mm Hg for sildenafil patients and 112/65±7/6 mm Hg for saffron patients, representing a mean BP decrease of 14.7 mm Hg (11.1% mean systolic BP decrease, 9.7% mean diastolic BP decrease). The difference in mean BP between treatment groups was significant for systolic and diastolic blood pressures (P=0.03). Mean heart rate at baseline was 69±4 and 70±4 min−1 in sildenafil and saffron groups, respectively. This increased to 12.8% with saffron (perhaps due to reduced blood pressure) and decreased by 8.6% with sildenafil (P=0.03). Serial hematological laboratory test showed decreases in peripheral blood leukocyte, red blood cell and platelets with saffron supplementation. Peripheral blood leukocyte, red blood cell and platelets decreased by 18.7, 15.6 and 17.8%, respectively (P=0.01). These decreases were not significant clinically, but can be potentially problematic with higher doses of saffron, or longer duration of saffron administration.

Table 5 The treatment emergent adverse events reported by 5% of patients

Discussion

The results of this prospective, open-label, crossover study demonstrate that treatment with saffron is not efficacious as oral medication for men with ED. To our knowledge, this report is the first published comparative study between sildenafil and saffron in men with ED who were naïve to therapy. The studied population was representative with respect to the population of men with ED at large. First of all, there was not a significant improvement in IIEF-EF domain as one of the main primary outcome measure. The difference in IIEF-EF domain improvement between sildenafil and saffron patients at the EOT was 76.1%. Similarly, at the EOT, 74.1 and 21.6% of patients in the sildenafil and saffron groups, respectively, reported of successful intercourse. In addition, responses to the GEQ showed that 60 mg saffron daily did not improve EF significantly.

In response to recent advances in synthetic medication for ED, there has been a renewed interest in medicinal plants in the treatment of sexual dysfunction.19 Multiple nutritional or herbal medicines have been proposed for the treatment of ED. However, because of the lack of well-designed, placebo-controlled trials, their efficacy remains questionable. Saffron is extensively recommended for treatment of impotence and for enhancement of sexual function in Iran. This recommendation is largely based on subjective opinion and rather than scientific observation.

ED often has a pronounced negative impact on self-confidence and quality of life, also affecting the spouse. However, increasing number of men are negative toward taking synthetic drugs for sexual disorders.20 This group of patients usually request ‘natural’ health products to improve their EF.21 In addition, a growing number of the world's population in different communities are turning to plant-derived remedies and medicines for many reasons. A survey revealed that 71% of Canadians and 19% of the adult population in the United States were using natural health products.22 Most of the herbal product users decide to consume herbal remedies derived from the conviction that these natural substances are safer than synthetic drugs, and is mainly based on personal sentence or information coming from friends or media.

In this study, the overall most sexual behavior parameters were remained unchanged or even deteriorated among the saffron group of patients compared with the sildenafil group. As detailed in the introduction section, only one pilot study trial of saffron in men with ED was identified.14 But, owing to major differences between our and the above-mentioned study, direct comparison of the results will be confusing. In the available literature, we could not find similar studies for comparison. This study also evaluated the treatment response to saffron by assessing the five IIEF domains of male sexual function, namely, EF, orgasmic function, sexual desire, intercourse satisfaction and overall satisfaction with sex life. There were no statistically significant improvements in all the five measured domains. This shows that none of the sexual aspects of male sexual function are affected by saffron.

Review of the literature reveals that there is not encouraging evidence for the use of nutritional and herbal medicines for treating sexual dysfunctions. Rigorous scientific studies on the safety of and efficacy of herbal products are often unavailable and this lack of knowledge may represent a serious problem, as patients may obtain different and unreliable information through websites and magazines. Herbal medicines should be used after documentation of their safety and efficacy through rigorous investigations and clinical trials. Finally, sildenafil is not a panacea, and the group of patients for whom this treatment is either contraindicated or ineffective is still being defined. Marketing data worldwide showed that dropout rates for sildenafil are as high as 50% of the patients treated.23

There are some limitations in this study; first, it was open label, second it takes place in only 12 weeks duration, and third we did not ask which pill the participants would rather take.

Conclusion

Saffron is commonly used in Iran for the treatment of impotence. As such, the results of the current study do not support the use of saffron in men with ED.

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Correspondence to M R Safarinejad.

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Safarinejad, M., Shafiei, N. & Safarinejad, S. An open label, randomized, fixed-dose, crossover study comparing efficacy and safety of sildenafil citrate and saffron (Crocus sativus Linn.) for treating erectile dysfunction in men naïve to treatment. Int J Impot Res 22, 240–250 (2010). https://doi.org/10.1038/ijir.2010.10

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Keywords

  • sildenafil
  • ED
  • treatment
  • sildenafil citrate
  • saffron
  • C. sativus
  • aphrodisiac

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