Safety and Efficacy of the Herbal Drug Hypericum Perforatum for the Treatment of Premature Ejaculation

Abstract

INTRODUCTION: Premature ejaculation (PE) is one of the most prevalent forms of male sexual dysfunction. The benefits of Hypericum perforatum for treatment of PE are unknown, although it is hypothesized that its effect on depression and neurotransmitter activity may be beneficial. The authors assessed the efficacy and safety of H. perforatum for the treatment of PE. METHODS: A prospective, double-blind, randomized, placebo-controlled design was used. Participants were 50 married men with PE. They were 18-50 years old and were evaluated between January 2007 and December 2008. Patients were randomly assigned to one of 2 equal groups. Group 1 received 3 daily tablets of hypericum extract (150 mg per tablet). Each tablet contained 160μg of hypericin. Group 2 received a placebo. All participants recorded intravaginal ejaculation latency time (IELT) and completed the International Index of Erectile Function (IIEF-5) questionnaire before and after treatment. Side effects were self-reported using a questionnaire. Results were compared using chi-square and paired t tests. RESULTS: Forty-two patients completed the study. Hypericum extract was discontinued due to anejaculation (n = 2) and erectile dysfunction (n = 1); 5 patients taking the placebo were lost to follow-up. There was a significant group difference in mean IELT (P < .001); IELT increased from 1.17 minutes to 5.8 minutes in the group taking hypericum extract. Patients taking hypericum extract also had significantly higher IIEF-5 ratings for the measures of intercourse satisfaction and overall satisfaction (P < .001). There were no significant group differences in mean IIEF-5 ratings of orgasmic function, erectile function, or sexual desire. Mild adverse events of headache, constipation, and photosensitivity were seen in 6 patients (27%) taking hypericum extract. CONCLUSION: H. perforatum (St. John's wort) may be an effective and safe treatment for PE, possibly because of its effect on neurotransmitters such as serotonin.

Full text

©2010 UroToday International Journal / Vol 3 / Iss 3 / June
doi:10.3834/uij.1944-5784.2010.06.21
http://www.urotodayinternationaljournal.com
ISSN 1944-5792 (print), ISSN 1944-5784 (online)
Seyyed Alaeddin Asgari, Siavash Falahatkar, Seyed Hosein Hoseini Sharifi, Ahmad Enshaei, Michael Fariad Jalili,
Aliakbar Allahkhah
Urology Research Center, Guilan University of Medical Sciences, Razi Hospital, Rasht, Iran
Submitted April 24, 2010 - Accepted for Publication May 4, 2010
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Volume 3 - June 2010
Safety and Efficacy of the Herbal Drug Hypericum Perforatum
for the Treatment of Premature Ejaculation
Abbreviations and Acronyms
5HT = 5-hydroxytryptamine
IELT = intravaginal ejaculation latency time
IIEF-5 = International Index of Erectile
Function
PE = premature ejaculation
SJW = St. John’s wort
SSRI = selective serotonin reuptake
inhibitors
ABSTRACT
KEYWORDS: Hypericum perforatum; Premature ejaculation; IELT; IIEF-5; Drug
therapy.
CORRESPONDENCE: Siavash Falahatkar, MD, Urology Research Center, Guilan
University of Medical Sciences, Razi Hospital, Sardare Jangal Street, Rasht, Guilan
41448, Iran (falahatkar_s@yahoo.com).
CITATION: UroToday Int J. 2010 Jun;3(3). doi:10.3834/uij.1944-5784.2010.06.21
INTRODUCTION: Premature ejaculation (PE) is one of the most prevalent forms of male sexual dysfunction. The
benefits of Hypericum perforatum for treatment of PE are unknown, although it is hypothesized that its effect
on depression and neurotransmitter activity may be beneficial. The authors assessed the efficacy and safety of H.
perforatum for the treatment of PE.
METHODS: A prospective, double-blind, randomized, placebo-controlled design was used. Participants were 50
married men with PE. They were 18-50 years old and were evaluated between January 2007 and December 2008.
Patients were randomly assigned to one of 2 equal groups. Group 1 received 3 daily tablets of hypericum extract
(150 mg per tablet). Each tablet contained 160μg of hypericin. Group 2 received a placebo. All participants
recorded intravaginal ejaculation latency time (IELT) and completed the International Index of Erectile Function
(IIEF-5) questionnaire before and after treatment. Side effects were self-reported using a questionnaire. Results
were compared using chi-square and paired t tests.
RESULTS: Forty-two patients completed the study. Hypericum extract was discontinued due to anejaculation (n =
2) and erectile dysfunction (n = 1); 5 patients taking the placebo were lost to follow-up. There was a significant
group difference in mean IELT (P < .001); IELT increased from 1.17 minutes to 5.8 minutes in the group taking
hypericum extract. Patients taking hypericum extract also had significantly higher IIEF-5 ratings for the measures
of intercourse satisfaction and overall satisfaction (P < .001). There were no significant group differences in
mean IIEF-5 ratings of orgasmic function, erectile function, or sexual desire. Mild adverse events of headache,
constipation, and photosensitivity were seen in 6 patients (27%) taking hypericum extract.
CONCLUSION: H. perforatum (St. John’s wort) may be an effective and safe treatment for PE, possibly because of
its effect on neurotransmitters such as serotonin.
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©2010 UroToday International Journal / Vol 3 / Iss 3 / June
doi:10.3834/uij.1944-5784.2010.06.21
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ISSN 1944-5792 (print), ISSN 1944-5784 (online)
UroToday International Journal®
original study
Safety and Efficacy of the Herbal Drug Hypericum Perforatum for the Treatment of Premature Ejaculation
INTRODUCTION
Premature ejaculation (PE) is one of the most frequent male
sexual complaints. It is estimated that 20% to 30% of men
experience PE at some point in their lifetime; however, the
prevalence depends on the definition employed [1,2]. A
universally accepted definition of PE has yet to be established,
but the Diagnostic and Statistical Manual of Mental Disorders [3]
defines it as, “persistant or recurrent ejaculation with minimal
sexual stimulation before, on, or shortly after penetration and
before the person wishes it.” PE frequently leads to marked
distress or interpersonal difficulty.
Intravaginal ejaculation latency time (IELT) is the numerical
indicator most frequently used to assess PE treatments during
clinical trials [4-6]. An IELT of < 2 minutes has been considered
consistent with the diagnosis of PE [7].
Pharmacological treatment of PE includes selective serotonin
reuptake inhibitors (SSRIs), tricyclic antidepressants,
phosphodiesterase (PDE) inhibitors, and topical anesthetics [8-
10]. Hypericum perforatum (H. perforatum), also known as St.
John’s wort (SJW), is a widely used over-the-counter drug for
treatment of depression. Its increase in popularity seems to
indicate a growing need for an alternative drug that may be able
to avoid the undesirable adverse effects associated with some
of the most commonly prescribed synthetic antidepressants.
SJW is widely prescribed in the United States and Europe,
and its use in other countries is increasing [11]. It is by far the
most commonly prescribed antidepressant in Germany, where
physicians prescribe it 4 times more often than fluoxetine.
A meta-analysis published in 2001 [12] analyzed 22 randomized
controlled trials and concluded that SJW is significantly
more effective than placebo and as effective as standard
antidepressants in the treatment of depression. Two double-
blind randomized controlled studies compared SJW with 2
SSRIs (fluoxetine and sertraline). Both studies found similar
clinical improvements in depressive symptoms as evidenced by
significantly reduced scores on the Hamilton Rating Scale for
depression [13,14]. Several randomized-sample studies [13,15]
have shown that H. perforatum was more effective than a
placebo and at least as effective as imipramine and fluoxetine
in the treatment of mild to moderate depression. The studies
further showed that H. perforatum had more benefits than the
other drugs, including decreased side effects and an increased
ability of patients to tolerate the medication. However, some
limitations to the studies using H. perforatum have been
noted, and studies measuring the effect of Hypericum in major
depression have reported conflicting results [16].
Hypricin and hyperforin, 2 isolates of H. perforatum, are
among the most researched active components of SJW. They
have been found to inhibit synaptosomal uptake of several
neurotransmitters, including serotonin, norepinephrine, and
gamma-aminobutyric acid (GABA) [15,17,18].
Treatment of PE in the field of urology is challenging, but
antidepressive medications have been part of the standard
management protocol. The benefits of H. perforatum for
treatment of PE are unknown, although it is hypothesized that
its effect on depression and neurotransmitter activity may be
beneficial. Therefore, the purpose of the present investigation
was to assess the efficacy and safety of H. perforatum for the
treatment of PE.
METHODS
Participants
A total of 50 married men with PE presented to the authors’
urology clinic between January 2007 and December 2008. The
patients ranged in age from 18-50 years.
PE was defined as IELT of < 2 minutes, occurring more than 50%
of the time while attempting sexual intercourse, and causing
significant distress for the patient and his partner. The diagnosis
was made by a physician. Patients were included if they had a
stable sexual relationship with a female sexual partner for at
least 1 year and had sexual intercourse more than once a week.
Exclusion criteria included: (1) patients with psychiatric
disorders or concurrent erectile dysfunction; (2) patients taking
medication known to impair sexual function; (3) patients with
a history of previous pelvic or spinal surgery, chronic prostatitis,
or urethritis; (4) patients with other sexual disorders such as
decreased libido; (5) patients receiving other treatments for PE.
Procedures
The study was approved by the ethics committee of the authors’
institution. A prospective, randomized, double-blind, placebo-
controlled design was used.
Patients were randomly assigned to one of 2 equal groups by
blocked random allocation sequence. The mean age of the
patients in group 1 and group 2 was 30.68 years and 31.7 years,
respectively.
Patients in group 1 were treated with 3 daily tablets of
Hypericum extract (Goldarou Comp. Isfahan), given at a dose of
150 mg per tablet. Each tablet contained 160μg of hypericin.
Patients in group 2 received identical placebo pills that did not
appear to be factitious. Participants in both groups received
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©2010 UroToday International Journal / Vol 3 / Iss 3 / June
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original study
Seyyed Alaeddin Asgari, Siavash Falahatkar, Seyed Hosein
Hoseini Sharifi, Ahmad Enshaei, Michael Fariad Jalili, Aliakbar Allahkhah
identical instructions. The medications were dispensed by a
pharmacologist who did not know the purpose of the research.
The investigators did not know which individual patients were
receiving the placebo or the Hypericum extract.
Before beginning treatment, all patients were asked to measure
IELT by using a stopwatch. They recorded the average IELT in
seconds from 3 consecutive separate occasions of intercourse.
All participants also completed the International Index of
Erectile Function (IIEF-5) questionnaire [19]. Thirty days after
completing the study, patients were asked to measure their
IELT and complete the IIEF-5 questionnaire a second time. Side
effects were self-reported using a questionnaire.
Data before and after treatment were compared using the
paired t test for continuous data and chi-square test for
categorical data. Because of the large number of paired
comparisons, a conservative probability level of P < .001 was
considered statistically significant. A power analysis was not
conducted. Therefore, the possibility of type II error exists with
this sample size.
RESULTS
Of the 50 original participants, 42 (84%) completed the
study (22 in group 1; 20 in group 2). In group 1, therapy was
discontinued due to anejaculation in 2 patients and erectile
dysfunction in 1 patient. In group 2, 5 patients did not return
to complete the study.
The mean age for patients in group 1 and group 2 was 30.7
years and 31.7 years, respectively, with no significant group
difference (P = .57). The mean duration of marriage for patients
in group 1 and group 2 was 3.7 years and 4.1 years, respectively,
with no significant group difference (P = .82).
Treatment Effects
Pretreatment Group Differences. Table 1 contains the
pretreatment means and standard deviations for the measures
of IELT and the 5 categories of the IIEF-5 (intercourse satisfaction,
overall satisfaction, orgasmic function, erectile function, sexual
desire) and the probability of significant group differences. The
mean IELTs were 70.23 seconds and 67.50 seconds for patients
in groups 1 and 2, respectively. These times are indicative of
PE. There were no significant pretreatment group differences
in any variable (P > .001).
Intragroup Effect of Drug Treatment. Table 2 contains the
means and standard deviations of the outcome measures before
and after receiving Hypericum extract and the probability of
significant differences due to treatment. After 4 weeks of
treatment, the mean IELT had significantly increased from
70.23 seconds (1.17 minutes) to 349.09 seconds (5.8 minutes)
(P < .001). There was also a significant increase in mean
ratings of intercourse satisfaction and overall satisfaction, and
a significant decrease in the mean rating of erectile function
(P < .001). There were no significant differences in orgasmic
function or sexual desire.
Intragroup Effect of Placebo Treatment. Table 3 contains
the means and standard deviations of the outcome measures
before and after receiving the placebo and the probability
of significant differences due to treatment. After 4 weeks of
placebo treatment, the mean IELT had significantly increased
from 67.5 seconds to 99 seconds (P < .001). There was also a
significant decrease in the IIEF-5 variable of erectile function
(P < .001). There were no placebo treatment effects for the
remaining IIEF-5 variables.
Group Differences in Treatment. Table 4 contains the means
and standard deviations of the outcome measures following
treatment with Hypericum extract or the placebo, and the
probability of significant group differences. There were
significant group differences in mean IELT (P < .001); patients
taking the Hypericum extract had a significantly longer
IELT than the patients taking the placebo. Patients taking
Hypericum extract also had significantly higher IIEF-5 ratings for
the measures of intercourse satisfaction and overall satisfaction
Measure Group Mean SD P
Intravaginal ejaculation
latency time (s)
Drug 70.23 21.07 .68
Placebo 67.50 21.18
Intercourse satisfaction (score) Drug 3.59 1.01 .34
Placebo 3.25 1.25
Overall satisfaction (score) Drug 9.59 1.26 .91
Placebo 9.55 1.00
Orgasmic function (score) Drug 9.41 0.50 .06
Placebo 9.15 0.37
Erectile function (score) Drug 27.14 1.61 .71
Placebo 26.95 1.57
Sexual desire (score) Drug 9.82 0.39 .88
Placebo 9.80 0.41
Table 1. Pretreatment Means and Standard Deviations
(SD) of Outcome Measures for Patients Receiving
Hypericum Extract (n = 22) and a Placebo (n = 20);
Probability of Significant Group Differences.
doi: 10.3834/uij.1944-5784.2010.06.21t1
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©2010 UroToday International Journal / Vol 3 / Iss 3 / June
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Safety and Efficacy of the Herbal Drug Hypericum Perforatum for the Treatment of Premature Ejaculation
(P < .001). There were no significant group differences in mean
orgasmic function, erectile function, or sexual desire.
Adverse Events
Adverse events were seen in 6 patients (27%) taking
Hypericum extract: headache (n = 3), constipation (n = 2), and
photosensitivity (n = 1). None of these 6 patients discontinued
treatment. There was 1 report of nausea in the patients taking
the placebo.
DISCUSSION
PE is ejaculation occurring without the control or desire of the
Table 2. Means and Standard Deviations (SD) of Outcome
Measures Before and After Treatment for Patients
Receiving Hypericum Extract (n = 22); Probability of
Significant Differences.
doi: 10.3834/uij.1944-5784.2010.06.21t2
Measure Time Mean SD P
Intravaginal ejaculation
latency time (s)
Before 70.23 21.07 <.001
After 349.09 119.16
Intercourse satisfaction
(score)
Before 3.59 1.01 <.001
After 7.32 1.32
Overall satisfaction (score) Before 9.59 1.26 <.001
After 12.68 1.13
Orgasmic function (score) Before 9.41 0.50 .042
After 9.23 0.43
Erectile function (score) Before 27.14 1.61 <.001
After 25.18 1.44
Sexual desire (score) Before 9.82 0.39 .083
After 9.95 0.21
Table 3. Means and Standard Deviations (SD) of Outcome
Measures Before and After Treatment for Patients
Receiving the Placebo (n = 20); Probability of Significant
Group Differences.
doi: 10.3834/uij.1944-5784.2010.06.21t3
Measure Time Mean SD P
Intravaginal ejaculation
latency time (s)
Before 67.5 21.18 <.001
After 99 37.26
Intercourse satisfaction (score) Before 3.25 1.25 .008
After 3.75 1.37
Overall satisfaction (score) Before 9.55 1.00 .014
After 10.05 0.89
Orgasmic function (score) Before 9.15 0.37 .01
After 9.45 0.51
Erectile function (score) Before 26.95 1.57 <.001
After 25.8 1.61
Sexual desire (score) Before 9.8 0.41 .163
After 9.7 0.57
Measure Group Mean SD P
Intravaginal ejaculation
latency time (s)
Drug 349.09 119.16 <.001
Placebo 99 37.26
Intercourse satisfaction (score) Drug 7.32 1.32 <.001
Placebo 3.75 1.37
Overall satisfaction (score) Drug 12.68 1.13 <.001
Placebo 10.05 0.89
Orgasmic function (score) Drug 9.23 0.43 .136
Placebo 9.45 0.51
Erectile function (score) Drug 25.18 1.44 .196
Placebo 25.8 1.61
Sexual desire (score) Drug 9.95 0.21 .073
Placebo 9.7 0.57
Table 4. Posttreatment Means and Standard Deviations (SD) of Outcome Measures
for Patients Receiving Hypericum Extract (n = 22) and a Placebo (n = 20); Probability
of Significant Group Differences. doi: 10.3834/uij.1944-5784.2010.06.21t4
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original study
Seyyed Alaeddin Asgari, Siavash Falahatkar, Seyed Hosein
Hoseini Sharifi, Ahmad Enshaei, Michael Fariad Jalili, Aliakbar Allahkhah
patient, and the diagnosis should only be made when there is
marked distress [20]. PE is one of the most prevalent sexual
dysfunctions in males and is reported to be more prevalent
than erectile dysfunction [21]. Although some biological and
psychological conditions have been proposed as contributing
to PE, the exact pathogenesis remains to be clarified [22].
Pharmacologic treatment for certain ejaculatory disorders
exists, such as the off-label use of SSRIs for PE. Recent research
has elucidated more about the role of serotonin and dopamine
at the central level in the physiology of both arousal and
orgasm [23]. There has been emphasis on identifying the
biological basis of ejaculation and its dysfunction. At present,
the most studied neurotransmitter in the neurophysiology of
ejaculation seems to be 5-hydroxytryptamine (serotonin) [23].
In contrast to the presynaptic 5-HT1a autoreceptors, the 5-HT1b
and 5-HT2c receptors have been shown to prolong ejaculatory
latency [24].
The exact physiological mechanisms contributing to the
positive results of Hypericum extract on PE in the present
study are not known and require further study. However,
the authors hypothesize that its effect on neurotransmitters
may have been involved. Preclinical studies have found that
SJW inhibits the synaptic reuptake system of serotonin and
norepinephrine [25-27]. Most of this herb’s pharmacological
activities are attributable to hypericin and hyperforin [26].
SJW up-regulates serotonin receptors and also has a significant
affinity for opiate sigma receptors, which may contribute to its
antidepressant effect [27]. The antidepressant effect of SJW
may also be mediated via reduction of corticotropin-releasing
hormone (CRH) secretion, through suppression of interleukin-6
(IL-6) release [28].
There exists some controversy about whether or not SJW
interferes with the action of other prescribed medications.
Will-Shahab et al [19] reported that reduced-hyperforin SJW
preparations are less likely to interact with drugs and may
substantially lower the risk of serious herb-drug interactions.
Studies have been designed to investigate the effects of a
specific SJW extract (Ze 117) on the pharmacokinetics of
ethinylestradiol and 3-ketodesogestrel, which are the 2
pharmacologically effective components of the low-dose
contraceptive Lovelle [19,29,30]. The authors reported that
the intake of reduced-hyperforin SJW preparations is less
likely to interact with drugs and may substantially lower the
risk of serious herb-drug interactions. However, another study
showed the risk of interactions of SJW with other drugs and the
possible mechanisms of these interactions [31]. For example,
SJW extracts may interact with the hormonal components of
oral contraceptives, thus causing spotting or break-through
bleeding. Additional studies are needed to show whether or
not SJW is a benign treatment.
In an observational study undertaken in 2007, Schulz [32]
reported an incidence of adverse events between 1-3% for
SJW, which was 10 times less frequent than those commonly
associated with synthetic antidepressants. The adverse effects
of SJW were found to include headache, itching, dizziness,
constipation, and fatigue [33]. In the present study, SJW
was effective on PE and had minor side effects of headache,
constipation, and photosensitivity. Reported complications
were fewer than those reported elsewhere from SSRIs such as
fluoxetine and sertraline.
CONCLUSION
Hypericum extract significantly increased IELT and significantly
improved some subjective scores on the IIEF-5 questionnaire,
possibly due to its effect on neurotransmitters such as serotonin.
It had few associated side effects when compared with
classically used antidepressants. These results suggest that H.
perforatum might be an effective and safe treatment modality
for PE. Additional studies with larger numbers of patients and
longer follow-up are needed to confirm this conclusion.
Conflict of Interest: none declared
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©2010 UroToday International Journal / Vol 3 / Iss 3 / June
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original study
Seyyed Alaeddin Asgari, Siavash Falahatkar, Seyed Hosein
Hoseini Sharifi, Ahmad Enshaei, Michael Fariad Jalili, Aliakbar Allahkhah
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