Efficacy and safety of eight-week therapy with Ashwagandha root extract in improvement of sexual health in healthy men: Findings of a prospective, randomized, double-blind, placebo-controlled study

Abstract

Background

Ashwagandha, a traditional Indian Ayurvedic remedy, an adaptogen, may improve sexual dysfunction in men and women.

Objective

This 8-week prospective, double-blind, randomized, placebo-controlled study evaluated the efficacy and safety of Ashwagandha Root Extract (ARE) on improving sexual health in healthy adult men.

Method

A total of 100 healthy men aged 30–50 years were randomly assigned to receive ARE 300 mg twice daily (n = 50), or identical placebo (n = 50) in a 1:1 ratio for 8 weeks. Study assessments such as Satisfying Sexual Events (SSEs), the Sexual Desire Inventory (SDI-2), the International Index of Erectile Function (IIEF) score, semen parameters and the Quality of Life (QOL) were done using the SF-12 tool at baseline, week 2, week 4, and week 8. Three participants from ARE and four participants from the placebo group were excluded due to follow-up loss. The efficacy analyses were done on Per-Protocol (PP) dataset of 93, whereas safety analyses were done on all 100 participants.

Results

Significant improvements were observed with ARE for semen volume (p = 0.005), sperm number (p = 0.006), sperm concentration (p = 0.007), and sperm morphology (p = 0.007). The improvement in scores was better with ARE for SDI-2 (p < 0.05), orgasm and sexual desire domains of IIEF (p < 0.05), and SF-12 (p < 0.0001). No adverse events were reported in the study.

Conclusion

Ashwagandha improved the orgasmic function, sexual desire and overall sexual satisfaction with the 8-week of oral administration. It was well tolerated as it showed no significant changes in hepatic and renal parameters in blood.

1. Introduction

Sexual desire, sexual activity, and sexual satisfaction are important aspects of human life, and these contribute to the quality of life for both men and women [1]. Male sexual dysfunction (MSD) or impaired sexual functioning includes a variety of conditions, including low libido, erectile dysfunction (ED), Peyronie's disease (PD), and premature ejaculation (PE) [2]. The prevalence of MSD increases with age and is relatively high (>50 %) in men aged 40–70 years [3,4]. Among the sexual dysfunctions, premature ejaculation and erectile dysfunction are the most prevalent types [5]. Low sexual desire includes a lack of interest in thinking about sex or in being sexual, either alone or with a partner [6]. Lifestyle disorders like obesity and dyslipidemia, along with excess smoking and alcohol can contribute to MSD [[7], [8], [9]]. Sexual dysfunction in men can be caused by various systemic diseases and medication. Long-term use of drugs like antihypertensives, antidepressants, diuretics, antiandrogens, opioids, anti-parkinsonians and sympathetic blockers can cause MSD [10]. For the MSD, the psychological effects on people and those in their vicinity can be profound. Overall prevalence of ED is 3–76.5 % [11,12].

Ashwagandha [Withania somnifera, (WS) fam. Solanaceae)], also called ‘Indian Winter Cherry’ or ‘Indian Ginseng’, is an adaptogenic herb used in Ayurveda, the traditional Indian medical system [13]. For centuries, it has been utilized as a ‘Rasayana’ and recognized for its various health benefits [14,15]. Different investigators have reported that Ashwagandha is beneficial in the treatment of male infertility [16,17]. Experimental studies have shown that treatment with Ashwagandha induced testicular development and spermatogenesis in immature Wistar rats by directly affecting the seminiferous tubules, improves the prosexual behavior of sexually sluggish mice, and increases testicular daily sperm production and serum testosterone level [18,19]. It has been well documented that high levels of reactive oxygen species (ROS) in the semen induce oxidative damage to the sperm and are associated with abnormal sperm parameters leading to infertility [20,21].

Ashwagandha has been found to counteract the formation of ROS in infertile men. The topic of male dysfunction remains relatively underexplored and is often considered a taboo subject. As a result, there is a significant gap in public awareness and scientific understanding. It is therefore crucial to conduct research and clinical trials to enhance knowledge in this area, promote awareness, and foster open discussions.

Considering, the probable benefit of ashwagandha extract supplementation on sexual wellness, this clinical study was conducted to evaluate the efficacy and safety of treatments with Ashwagandha Root Extract (ARE) in improving male sexual health. The study provides updated and comprehensive data on the effects of ARE therapy on sexual health parameters, semen analysis, and quality of life in men.

2. Methods

2.1. Study design and setting

This was an 8-week treatment period, prospective, randomized, double-blind, placebo-controlled study in healthy men. Participants who met the criteria for inclusion and exclusion were allocated to either of the two treatment groups. The study and related documents were reviewed and approved by the Institutional Ethics Committee (DYP/IEC/14/2022; dt. 26-08-2022). Written informed consent was obtained in preferable languages (Hindi, Marathi, and English) from all participants prior to the enrolment. Each participant was explained in detail about the study objective and the expected outcome before taking the consent. The study adhered to the Good Clinical Practice (GCP) guidelines, New Drugs and Clinical Trials 2019 (India), and the Declaration of Helsinki (Taipei 2016). It also registered with the clinical trials registry of India [# CTRI/2022/09/045646; dt: 19/09/2022).

2.2. Study participants

2.2.1. Inclusion criteria

The study sample consisted of 100 otherwise healthy men between 30 and 50 years of age visiting the study sites for seeking interventions for their sexual problems. Men with poor sexual satisfaction on self-perception for a minimum of the previous three months were screened for study. Those with baseline total scores between 11 and 16 on IIEF-EF (International Index of Erectile Function – Erectile Function) scale and in a stable, monogamous, heterosexual relationship were enrolled. Men willing to refrain from other ED treatments during the study or for improving sexual performance during the study period were considered as an inclusion. All participants and their partners were required to be physically present for at least 50 % of each calendar month, willing to engage in regular sexual intercourse, and used medically approved form of contraception throughout the study. Men were required to have a compliant partner who was willing to observe study procedures. The study expected the participants to attempt sexual intercourse at least four or more times in two weeks. Men having sufficient understanding to communicate effectively with the investigator, are willing to discuss their sexual functioning and follow protocol requirements for 8 weeks with the investigative staff were enrolled.

2.2.2. Exclusion criteria

Men with any acute illness, those with a clinically significant medical history, or conditions that could jeopardize safety or study validity were not enrolled. Participants will be excluded if they have used any medications or supplements for sexual function (e.g., ginseng, Sildenafil) in the past 3 months, have significant medical, psychiatric, or neurological conditions that could affect safety or study validity, or are involved in other clinical trials or dietary studies. Additional exclusions include a history of hypersensitivity, anatomical penis malformations, primary hypoactive sexual desire, ED due to other disorders (e.g., hypopituitarism, hypothyroidism), spinal injury, failed pelvic surgery, penile implants, malignancy, alcohol or drug addiction, and if their partner plans to conceive within six months. Participants who have recently participated in another clinical trial or plan to father a child or have a pregnant partner will also be excluded.

2.3. Randomization and blinding

Enrolled participants were randomly assigned to ARE or placebo in 1:1 randomization ratio. Randomization was performed using a computer-generated pre-determined randomization list. The study products, including both the active treatment and placebo, were identical in form and color. To ensure blinding in this double-blind study, sequentially numbered opaque sealed envelopes (SNOSE) were utilized. Both the subjects and the research team, including staff and investigators, remained unaware of the treatment assignments. The randomization codes were securely held by the investigator, and neither the study site staff (except for the principal investigator) nor the study monitor had access to these codes until the study concluded. The code could only be accessed in case of an emergency. An independent researcher, who was blinded to the treatment assignments, collected the assessment results at each scheduled appointment.

2.4. Interventions

The ARE group received capsule containing 300 mg ARE (KSM-66 Ashwagandha, Ixoreal Biomed Inc., Los Angeles, California, USA) orally twice daily after breakfast and dinner (preferably 30 min before the anticipated sexual intercourse) with a glass of water or milk for a period of eight weeks. The placebo group received identical placebo capsule (300 mg starch) for similar period. All men were asked to continue their routine diet and physical activities during the study period.

2.5. Study outcomes

2.5.1. Primary outcome

Primary study outcome was the mean change in scores for the Satisfying Sexual Events (SSEs) scale from baseline to week 8.

2.5.2. Secondary outcomes

The secondary efficacy outcomes were mean changes in scores for the Sexual Desire Inventory – version 2 (SDI-2), International Index of Erectile Dysfunction (IIEF), semen parameters, serum sex hormones (testosterone, dihydrotestosterone (DHT), follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, and Quality of Life (QoL) using the SF-12 (Short Form 12) questionnaire.

2.6. Study assessments

A thorough physical examination and vital signs were assessed during site visits at baseline, week 2, week 4 and week 8.

2.6.1. Satisfying sexual events (SSE)

The SSE were self-reported by men for total number of intercourse events (sexual and non-sexual), number of orgasms, and number of satisfying sexual activities [22]. The sexual activity was recorded for the 2-week period prior to the assessment date and were based on recall by participant at baseline assessment. For follow-up assessments, sexual activity diary was maintained. Sexual desire levels were recorded for 24 h prior to visit on a four-point Likert scale (0 = No desire, 1 = Mild desire, 2 = Moderate desire and 3 = Strong desire).

2.6.2. Sexual Desire Inventory 2 (SDI-2)

SDI-2 is a brief 14-item scale which is based on the select items using theoretical models of desire, and diagnostic criteria used in the DSM–III–R for Hypoactive Sexual Desire Disorder (HSDD), and clinical experience in assessing and treating sexual desire disorders [23]. The Higher scores indicate stronger sexual satisfaction.

2.6.3. International Index of erectile dysfunction (IIEF)

IIEF is a 15-item validated, multi-dimensional, self-administered questionnaire commonly used in the clinical assessment of erectile dysfunction and treatment outcomes in clinical study [24]. The scoring of 0–5 is marked for 15 questions that assess the four domains which are Erectile Function (EF), Orgasmic Function (OF), Sexual Desire (SD), and Intercourse Satisfaction (IS). Sum of scores of the four domain yields the total IIEF score.

2.6.4. Short Form 12 (SF-12)

The SF-12 is a self-reported outcome measure assessing the impact of health on an individual's everyday life and is often used as a quality-of-life measure [25]. The SF-12 uses the same eight domains as the original SF-36 scale of 36 items.

2.6.5. Semen analysis and laboratory tests

Laboratory tests and semen analysis were done at baseline and week 8. Standard manual semen analysis was performed according to World Health Organization (WHO) guidelines [26]. The semen sample was collected after a minimum of 2 days of sexual abstinence. Semen parameters included semen volume (mL), sperm count (X 10⁶ per mL), total sperm count in ejaculate (X 10⁶), total sperm motility (%), pH, sperm vitality (% of vital sperms), and normal sperm morphology (%). Blood samples were collected and tested using the chemiluminescence method at screening to estimate the levels of serum testosterone, DHT, FSH, LH and prolactin.Other serum tests for safety were hemoglobin (Hb), creatinine, blood urea nitrogen (BUN), bilirubin (total and direct), proteins (albumin, globulin, A:G ratio), alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP).

2.7. Sample size

Sample size calculations were performed based on the reported data for improvement in SDI scores with a polyherbal formulation. A total sample size of 92 (46 in each arm) was deemed necessary to attain 80 % statistical power and maintain a 2.5 % (one-sided) significance level to detect a difference of 24.12 between herbal treatment and placebo for total SDI score. We enrolled 100 cases in the study to account for potential 10 % dropouts.

2.8. Statistical analysis

We employed summary statistics to summarize continuous variables and other demographic characteristics (Age, weight, and BMI), which included the number of observations, mean, and standard deviation with a 95 % confidence interval (for normally distributed data). Data for continuous variables were analyzed for differences between the two groups at each time point using independent sample t-test. Between group comparisons with baseline and follow-up data were analyzed using repeat measures Analysis of Variance (ANOVA). For ordinal data of sexual desire scores, Mann-Whitney ‘U’ test is used for between group comparisons. The two-sample t-test was used to compare the mean differences between ARE and Placebo groups at each time point for continuous outcomes (e.g., serum hormones, semen parameters, IIEF scores).

3. Results

A total of 133 men were screened, of which 100 were enrolled in the study (CONSORT flow chart, Fig. 1). The per-protocol (PP) dataset was used for efficacy analysis, which included 93 patients (47 ARE and 46 placebo) who completed the study as per protocol. The safety dataset was the intent-to-treat (ITT) dataset which included all 100 men who were randomized and received study medication.

Fig. 1.

CONSORT flow chart

The CONSORT flow chart represents the participant flow throughout the study.

3.1. Baseline data

The two groups (ARE and placebo) were similar (p > 0.05) with respect to demography, Body Mass Index (BMI) and vital parameters in both ITT and PP datasets (Table 1). There were no differences (p > 0.05) between the two groups with respect to the baseline data for all parameters, including semen analysis, serum hormones, IIEF, SDI-2, sexual events, and SF-12 in both PP and ITT datasets (Table 2).

Table 1.

Demography and vital parameters at baseline ITT (n = 100) and PP dataset (n = 93).

		ITT dataset (n = 100)					PP dataset (n = 93)
					2-sample t-test					2-sample t-test
	Treatment	N	Mean	SD	t	p	N	Mean	SD	t	p
Age (yrs.)	ARE	50	35.64	9.67	1.302	0.196	47	35.91	9.89	1.341	0.183
	Placebo	50	33.54	6.04			46	33.61	6.25
SBP (mm Hg)	ARE	50	117.80	4.67	−0.358	0.721	47	117.89	4.61	0.002	0.998
	Placebo	50	118.14	4.82			46	117.89	4.95
DBP (mm Hg)	ARE	50	80.20	5.57	−0.253	0.800	47	80.09	5.59	−0.191	0.849
	Placebo	50	80.48	5.47			46	80.30	5.50
Pulse rate (per min.)	ARE	50	78.79	7.40	0.223	0.824	47	78.94	7.56	0.127	0.900
	Placebo	50	78.52	4.03			46	78.78	4.07
Respiratory rate (per min.)	ARE	50	17.14	1.09	−1.195	0.235	47	17.09	1.10	−1.307	0.194
	Placebo	50	18.94	10.60			46	19.20	11.01
BMI (kg/sq.m)	ARE	50	25.58	4.75	−1.183	0.240	47	25.34	4.78	−1.325	0.188
	Placebo	50	26.60	3.79			46	26.54	3.92

ARE: Ashwagandha root extract; BMI: Body mass index; ITT: Intent to treat; PP: Per protocol; SD: Standard deviation.

Table 2.

Serum sex hormones, semen parameters and sexual activity parameters at baseline (n = 93).

		ITT dataset (n = 100)					PP dataset (n = 93)
					2-sample t-test					2-sample t-test
	Treatment	N	Mean	SD	t	p	N	Mean	SD	t	p
Serum hormone levels
Testosterone (ng/dL)	ARE	50	492.11	297.27	−0.025	0.980	47	489.97	301.18	−0.058	0.954
	Placebo	50	493.49	241.99			46	493.30	249.75
Dihydrotestosterone (pg/mL)	ARE	50	354.80	231.86	0.055	0.956	47	360.73	237.10	−0.019	0.985
	Placebo	50	351.40	370.73			46	361.99	384.49
FSH (IU/L)	ARE	50	7.53	6.14	0.459	0.647	47	7.35	5.80	0.117	0.907
	Placebo	50	7.00	5.46			46	7.21	5.64
LH (IU/L)	ARE	50	6.31	4.22	−0.602	0.548	47	6.35	4.27	−0.583	0.561
	Placebo	50	6.81	4.16			46	6.87	4.31
Prolactin (ng/mL)	ARE	50	15.43	8.10	−0.256	0.799	47	14.93	7.84	0.204	0.839
	Placebo	50	15.89	9.54			46	14.61	6.94
Semen parameters
Semen volume (mL)	ARE	50	1.76	1.52	−0.593	0.555	47	1.74	1.57	−0.501	0.618
	Placebo	50	1.91	0.95			46	1.88	0.97
Sperm count (X106 per mL)	ARE	50	21.72	21.43	0.497	0.620	47	21.25	22.16	0.319	0.751
	Placebo	50	19.53	20.35			46	19.73	21.14
Sperm number (X106 per ejaculate)	ARE	50	41.53	45.62	0.074	0.941	47	40.45	47.15	−0.046	0.964
	Placebo	50	40.85	42.67			46	40.91	44.18
Sperm motility (%)	ARE	50	24.37	16.68	−0.685	0.495	47	23.60	16.39	−0.273	0.786
	Placebo	50	27.03	19.85			46	24.67	18.95
Semen pH	ARE	50	7.71	1.27	−0.460	0.647	47	7.65	1.30	−0.501	0.618
	Placebo	50	7.83	1.22			46	7.79	1.26
Sperm vitality (%)	ARE	50	33.79	21.33	−0.010	0.992	47	31.98	21.01	0.022	0.983
	Placebo	50	33.84	22.75			46	31.87	22.79
Sperm morphology (% normal)	ARE	50	20.48	15.53	0.522	0.603	47	19.60	15.75	0.288	0.774
	Placebo	50	18.49	20.16			46	18.43	20.50
Sexual desire inventory - 2
SDI-2 total score	ARE	50	58.20	14.90	0.253	0.801	47	57.77	15.24	0.157	0.875
	Placebo	50	57.52	11.77			46	57.33	11.41
Satisfying sexual events (SSE in past 2 weeks)
No. of intercourses	ARE	50	6.40	5.57	0.244	0.808	47	6.57	5.69	0.262	0.794
	Placebo	50	6.12	5.89			46	6.26	5.84
No. of non-sexual intercourses	ARE	50	6.84	8.04	−0.355	0.723	47	7.15	8.17	−0.034	0.973
	Placebo	50	7.30	4.37			46	7.2	4.43
No. of orgasms	ARE	50	1.44	2.66	0.889	0.376	47	1.4	2.71	0.685	0.495
	Placebo	50	1.00	2.28			46	1.04	2.36
No. of satisfying sexual activities	ARE	50	3.96	3.68	0.022	0.982	47	4.06	3.74	−0.115	0.908
	Placebo	50	3.94	5.19			46	4.17	5.34
Level of sexual desire	ARE	50	1.62	0.90	2.109	0.038	47	1.09	0.72	−0.014	0.989
	Placebo	50	1.26	0.80			46	1.09	0.59
IIEF
Erectile function	ARE	50	15.82	5.50	0.127	0.899	47	15.43	5.39	−0.147	0.883
	Placebo	50	15.70	3.80			46	15.57	3.58
Orgasmic function	ARE	50	5.84	2.16	0.000	1.000	47	5.83	2.19	−0.103	0.918
	Placebo	50	5.84	1.54			46	5.87	1.45
Sexual desire	ARE	50	5.80	1.43	−0.590	0.557	47	5.74	1.45	−0.411	0.682
	Placebo	50	6.00	1.93			46	5.89	1.96
Intercourse satisfaction	ARE	50	5.86	2.63	0.295	0.769	47	5.79	2.69	0.224	0.823
	Placebo	50	5.72	2.08			46	5.67	2.14
Total IIEF score	ARE	50	41.92	12.84	0.427	0.671	47	41.40	12.97	0.302	0.763
	Placebo	50	40.96	9.39			46	40.70	9.32
QoL
SF-12 total score	ARE	50	28.40	3.37	0.890	0.376	47	28.34	3.43	0.132	0.896
	Placebo	50	27.70	4.42			46	28.24	3.97

ARE: Ashwagandha root extract; PP: Per protocol; SD: Standard deviation; FSH: Follicle-Stimulating Hormone; ITT: Intent to treat; LH: Luteinizing Hormone; IIEF: International index of erectile dysfunction; ITT: Intent to treat; PP: Per protocol; QoL: Quality of life; SD: Standard deviation; SF-12: Short Form (12) Health Survey; SDI: Sexual Desire inventory.

3.2. Primary outcome

Greater improvement in the number of sexual events (p = 0.042), satisfying sexual events, orgasms, and sexual desire scores were observed with ARE compared to placebo (Fig. 2, Table 3).

Fig. 2.

Sexual activity at baseline and follow-up period

Graphical representation of various domains of the satisfying sexual events.

Table 3.

Change from baseline in serum sex hormones, semen parameters and sexual activity parameters in PP dataset (n = 93).

			Change from baseline		Mean Difference	95 % C.I. of the difference		2-sample t-test
	Treatment	N	Mean	SD		Lower	Upper	t	p
Serum hormones (Week 8)
Serum testosterone (ng/dL)	ARE	47	70.46	242.05	120.13	27.18	213.09	2.567	0.012
	Placebo	46	−49.68	207.50
Dihydrotestosterone (pg/mL)	ARE	47	37.64	129.71	57.19	−64.99	179.36	0.930	0.355
	Placebo	46	−19.55	400.80
FSH (IU/L)	ARE	47	−0.19	1.70	−0.70	−2.18	0.79	−0.932	0.354
	Placebo	46	0.51	4.82
LH (IU/L)	ARE	47	0.29	2.21	1.12	−0.28	2.52	1.585	0.116
	Placebo	46	−0.83	4.29
Prolactin (ng/mL)	ARE	47	0.70	4.64	1.60	−0.31	3.50	1.663	0.100
	Placebo	46	−0.90	4.62
Semen parameters (Week 8)
Semen volume (mL)	ARE	47	0.45	0.93	0.50	0.16	0.85	2.906	0.005
	Placebo	46	−0.06	0.73
Sperm count (X106 per mL)	ARE	47	6.83	25.14	4.88	−2.58	12.33	1.300	0.197
	Placebo	46	1.96	3.96
Sperm count (X106 per ejaculate)	ARE	47	19.82	47.02	21.20	6.09	36.30	2.787	0.006
	Placebo	46	−1.38	21.40
Sperm motility (%)	ARE	47	8.87	19.46	4.95	−2.14	12.04	1.386	0.169
	Placebo	46	3.92	14.58
Semen pH	ARE	47	0.50	2.01	0.45	−0.14	1.05	1.518	0.133
	Placebo	46	0.04	0.29
Sperm vitality (% vital)	ARE	47	6.32	21.30	7.09	−0.21	14.38	1.930	0.057
	Placebo	46	−0.77	13.05
Sperm morphology (% normal)	ARE	47	4.33	12.33	6.13	1.75	10.51	2.779	0.007
	Placebo	46	−1.80	8.55
SDI-2 total score
Week 2	ARE	47	7.83	14.59	6.11	0.27	11.95	2.078	0.040
	Placebo	46	1.72	13.75
Week 4	ARE	47	12.96	15.57	9.20	3.00	15.39	2.949	0.004
	Placebo	46	3.76	14.47
Week 8	ARE	47	20.89	17.88	14.63	7.67	21.59	4.176	<0.0001
	Placebo	46	6.26	15.82
SSE
No. of intercourses
Week 2	ARE	47	2.09	4.02	2.23	0.56	3.9	2.658	0.009
	Placebo	46	−0.14	3.76
Week 4	ARE	47	3.7	3.92	0.92	−1.4	3.23	0.789	0.432
	Placebo	46	2.79	6.6
Week 8	ARE	47	8.25	6.03	2.75	0.11	5.39	2.068	0.042
	Placebo	46	5.5	6.3
No. of non-sexual intercourses
Week 2	ARE	47	−0.73	8.76	−3.25	−8.18	1.68	−1.311	0.194
	Placebo	46	2.52	13.8
Week 4	ARE	47	−0.57	7.11	0.27	−2.59	3.12	0.185	0.854
	Placebo	46	−0.83	6.15
Week 8	ARE	47	0.25	8.12	0.63	−2.53	3.79	0.397	0.693
	Placebo	46	−0.38	6.49
No. of orgasms
Week 2	ARE	47	0.27	3.76	0.15	−1.16	1.47	0.233	0.817
	Placebo	46	0.12	2.1
Week 4	ARE	47	2	3.22	0.48	−1.33	2.29	0.523	0.602
	Placebo	46	1.52	5.06
Week 8	ARE	47	4.82	6.61	2.34	−0.15	4.83	1.869	0.065
	Placebo	46	2.48	4.83
No. of satisfying sexual activities
Week 2	ARE	47	−0.52	5.31	−1.31	−3.32	0.7	−1.294	0.199
	Placebo	46	0.79	3.93
Week 4	ARE	47	0.55	5.61	−1.5	−3.85	0.84	−1.273	0.206
	Placebo	46	2.05	5.32
Week 8	ARE	47	4.39	7.23	0.7	−2.19	3.59	0.479	0.633
	Placebo	46	3.69	6.17
Level of sexual desire
Week 2	ARE	47	0.8	1.13	0.2	−0.27	0.67	0.845	0.400
	Placebo	46	0.6	1.06
Week 4	ARE	47	0.93	0.97	0	−0.44	0.45	0.015	0.988
	Placebo	46	0.93	1.09
Week 8	ARE	47	1.23	0.77	0.32	−0.04	0.69	1.749	0.084
	Placebo	46	0.9	0.93
IIEF
Erectile function
Week 2	ARE	47	2.70	4.67	1.14	−0.98	3.25	1.067	0.289
	Placebo	46	1.57	5.58
Week 4	ARE	47	3.77	6.09	2.51	−0.20	5.21	1.836	0.070
	Placebo	46	1.26	7.04
Week 8	ARE	47	1.87	9.83	1.22	−2.34	4.78	0.680	0.498
	Placebo	46	0.65	7.24
Orgasmic function
Week 2	ARE	47	0.49	2.39	1.08	0.22	1.93	2.510	0.014
	Placebo	46	−0.59	1.68
Week 4	ARE	47	0.43	2.61	0.27	−0.84	1.38	0.489	0.626
	Placebo	46	0.15	2.78
Week 8	ARE	47	1.11	3.67	1.78	0.38	3.18	2.522	0.013
	Placebo	46	−0.67	3.11
Sexual desire (IIEF)
Week 2	ARE	47	0.83	1.97	0.83	−0.01	1.67	1.972	0.052
	Placebo	46	0.00	2.09
Week 4	ARE	47	0.77	2.00	0.53	−0.55	1.60	0.971	0.334
	Placebo	46	0.24	3.12
Week 8	ARE	47	1.81	2.14	2.31	1.20	3.42	4.118	<0.0001
	Placebo	46	−0.50	3.17
Intercourse satisfaction
Week 2	ARE	47	0.83	2.68	−0.71	−1.76	0.33	−1.358	0.178
	Placebo	46	1.54	2.37
Week 4	ARE	47	1.72	3.53	0.46	−0.81	1.73	0.724	0.471
	Placebo	46	1.26	2.53
Week 8	ARE	47	1.68	3.32	0.62	−0.66	1.89	0.958	0.340
	Placebo	46	1.07	2.86
Total IIEF score
Week 2	ARE	47	5.79	9.21	2.85	−1.39	7.09	1.336	0.185
	Placebo	46	2.93	11.30
Week 4	ARE	47	7.21	14.25	4.13	−1.96	10.21	1.347	0.181
	Placebo	46	3.09	15.27
Week 8	ARE	47	7.55	22.51	6.34	−2.14	14.81	1.486	0.141
	Placebo	46	1.22	18.36
SF-12 total score
Week 2	ARE	47	2.23	4.75	1.26	−0.79	3.30	1.218	0.226
	Placebo	46	0.98	5.19
Week 4	ARE	47	2.70	4.07	1.98	−0.04	4.01	1.948	0.055
	Placebo	46	0.72	5.64
Week 8	ARE	47	4.40	4.13	5.40	3.30	7.51	5.100	<0.0001
	Placebo	46	−1.00	5.95

Note: Negative mean value indicates reduction, and positive value indicates increase in scores from baseline.

ARE: Ashwagandha root extract; PP: Per protocol; SD: Standard deviation; FSH: Follicle-Stimulating Hormone; ITT: Intent to treat; LH: Luteinizing Hormone; IIEF: International index of erectile dysfunction; ITT: Intent to treat; PP: Per protocol; SD: Standard deviation; SF-12: Short Form (12) Health Survey; SDI: Sexual Desire inventory, QoL: Quality of life.

3.3. Secondary efficacy outcomes

Table 3 presents the descriptives for the change from baseline for all parameters in the PP dataset. ARE therapy caused a greater increase (p<0.05) in SDI-2 scores from baseline after 2, 4, and 8 weeks. Men receiving ARE treatment had greater improvements in the orgasmic function (OF) domain of IIEF (p=0.013), sexual desire (SD) domain of IIEF (p<0.0001), and SF-12 QoL scores (p<0.0001) (supplementary material). ARE also led to a greater increase in semen volume (p=0.005), sperm count per ejaculate (p=0.007), and normal sperm morphology (p=0.007) compared to placebo.

3.4. Safety outcomes

During the study period, none of the participants reported any adverse events. Table 4 presents the descriptives for data for hematological, hepatic, and renal parameters (baseline and change after 8 weeks) in PP dataset (n = 93). No differences were observed in any of the laboratory parameters with ARE and placebo at the end of the 8-week therapy.

Table 4.

Hematological, hepatic and renal parameters (baseline and change after 8 weeks) in PP dataset (n = 93).

					Mean Diff.	95 % C·I.		2-sample t-test
	Treatment	N	Mean	SD		Lower	Upper	t	p
Hb (gm/dL)
Baseline	ARE	47	10.20	1.33	−0.06	−0.61	0.49	−0.212	0.833
	Placebo	46	10.25	1.34
Change at week 8	ARE	47	0.09	0.34	−0.03	−0.17	0.11	−0.431	0.667
	Placebo	46	0.12	0.34
Creatinine (gm/dL)
Baseline	ARE	47	0.68	0.21	−0.08	−0.17	0.00	−1.993	0.049
	Placebo	46	0.76	0.19
Change at week 8	ARE	47	−0.07	0.08	−0.03	−0.06	0.01	−1.423	0.158
	Placebo	46	−0.04	0.10
BUN (IU/L)
Baseline	ARE	47	19.20	1.33	−0.06	−0.61	0.49	−0.212	0.833
	Placebo	46	19.25	1.34
Change at week 8	ARE	47	0.37	1.14	−0.36	−0.89	0.17	−1.358	0.178
	Placebo	46	0.73	1.42
Bilirubin total (mg/dL)
Baseline	ARE	47	0.65	0.19	−0.01	−0.09	0.06	−0.335	0.739
	Placebo	46	0.66	0.17
Change at week 8	ARE	47	−0.07	0.07	−0.02	−0.06	0.01	−1.337	0.185
	Placebo	46	−0.05	0.09
Bilirubin direct (mg/dL)
Baseline	ARE	47	0.21	0.13	0.00	−0.05	0.06	0.072	0.943
	Placebo	46	0.21	0.14
Change at week 8	ARE	47	0.01	0.07	0.02	−0.01	0.05	1.591	0.115
	Placebo	46	−0.01	0.06
Protein (gm/dL)
Baseline	ARE	47	7.98	2.03	−0.56	−1.43	0.31	−1.282	0.203
	Placebo	46	8.54	2.19
Change at week 8	ARE	47	−0.23	0.17	−0.04	−0.14	0.07	−0.686	0.494
	Placebo	46	−0.19	0.30
Albumin (gm/dL)
Baseline	ARE	47	4.82	1.02	−0.27	−0.71	0.16	−1.244	0.217
	Placebo	46	5.09	1.10
Change at week 8	ARE	47	−0.14	0.14	0.01	−0.07	0.08	0.201	0.841
	Placebo	46	−0.15	0.21
Globulin (gm/dL)
Baseline	ARE	47	3.16	1.02	−0.29	−0.72	0.15	−1.316	0.191
	Placebo	46	3.45	1.10
Change at week 8	ARE	47	−0.08	0.06	−0.04	−0.08	−0.01	−2.280	0.025
	Placebo	46	−0.04	0.11
A-G Ratio
Baseline	ARE	47	1.56	0.14	0.05	0.00	0.11	2.034	0.045
	Placebo	46	1.51	0.12
Change at week 8	ARE	47	0.00	0.04	0.03	0.01	0.04	2.776	0.007
	Placebo	46	−0.03	0.04
ALT (IU/L)
Baseline	ARE	47	30.00	1.33	−0.06	−0.61	0.49	−0.212	0.833
	Placebo	46	30.05	1.34
Change at week 8	ARE	47	0.38	1.15	−0.36	−0.89	0.17	−1.337	0.185
	Placebo	46	0.73	1.42
AST (IU/L)
Baseline	ARE	47	30.20	1.33	−0.06	−0.61	0.49	−0.212	0.833
	Placebo	46	30.25	1.34
Change at week 8	ARE	47	0.38	1.15	−0.36	−0.89	0.17	−1.337	0.185
	Placebo	46	0.73	1.42
ALP (IU/L)
Baseline	ARE	47	89.99	4.00	−0.18	−1.83	1.47	−0.212	0.833
	Placebo	46	90.16	4.01
Change at week 8	ARE	47	0.38	1.15	−0.36	−0.89	0.17	−1.337	0.185
	Placebo	46	0.73	1.42

Note: Negative mean value for change indicates reduction, and positive value indicates increase from baseline.

ALP: Alkaline Phosphatase; ALT: Alanine Aminotransferase; ARE: Ashwagandha root extract; AST: Aspartate Aminotransferase; BUN: Blood Urea Nitrogen; C·I: Confidential interval; Hb: Haemoglobin; PP: Per Protocol; SD: Standard deviation.

4. Discussion

A possible mechanism by which Ashwagandha improves sexual performance could be its interaction with GABA receptors, which in turn may enhance the expression of gonadotropin-releasing hormone (GnRH). Furthermore, Ashwagandha may influence the reproductive system and fertility through its withanolides—steroidal lactone triterpenoids that share a structural similarity with testosterone [27,28]. We evaluated the efficacy and safety of an 8-week treatment with ARE in men attending an infertility clinic. One of the first studies of ARE (90-day treatment) was reported by Ambiye VR et al. (2013) in a randomized, placebo-controlled study involving 46 men with oligospermia (sperm count <20 million/mL) [18]. This pilot study involved men with oligospermia, and significant improvements (p < 0.05) in semen parameters were seen to the extent of 167 % for sperm count, 53 % for semen volume, and 57 % for sperm motility. Our study involved men with sperm counts on the lower side of the reference range, and we also observed a similar trend in the semen parameters after 8 weeks. With ARE the increase in semen volume was 25.56 % (p = 0.005), the sperm count was 47.72 % (p = 0.006), and the sperm vitality improved by 18.70 % (p = 0.007). Few of the patients in our study visited for infertility treatment and had a low sperm count, as well as a low sexual function. Although the sperm count levels were lower in these men, the serum testosterone levels were normal, and there was no hormonal disruption in any of the men included in the study.

Sexual function and sexual satisfaction are two of the most important outcomes of the male and female sexual dysfunction studies. Although benefits of ARE for female sexual function and satisfaction have been reported, no study has been reported for men [29]. We also observed improvements in serum testosterone (p = 0.012), DHT, prolactin, FSH, and LH levels. A systematic review of the effects of Withania somnifera on the reproductive system by Nasimi R. et al. (2018) reports that Ashwagandha improves reproductive system function by enhancing semen quality, enhancing enzymatic activity in seminal plasma, and decreasing oxidative stress [30]. Ashwagandha also improves the FSH and LH balance, leading to folliculogenesis and an increase in gonadal weight.

In contradiction to our findings, a randomized placebo-controlled trial did not observe any difference between ashwagandha root extract (n = 41) and placebo (n = 45) for change in IIEF scores in men with psychogenic erectile dysfunction [16]. The differences in the results could be due to the method of extract preparation and the lack of standardization of the end product. The ARE used in our study was the KSM-66 Ashwagandha, which uses a unique proprietary aqueous extraction process, based on “green chemistry” principles without using alcohol or any other chemical solvent. This extraction process yields the optimum percentage of withanolides, retaining the other important bioactives of the plant, which are required for the efficacy and safety of the herb. Psychological factors have an important role in sexuality and sexual satisfaction [1]. KSM-66 ashwagandha has a high withanolide content (>5 %), which helps fight stress by improving brain function, memory, and reproductive balance. It also makes the body more resistant to stress and boosts cell-mediated immunity. Hence, by virtue of its effects on stress, it may be beneficial for improving psychogenic sexual dysfunction.

A systematic review and meta-analysis described the results of 42 placebo-controlled clinical trials involving alternative medicines and herbal remedies in the management of erectile dysfunction (ED) [31] The authors concluded that Panax ginseng, Pygnogenol, Prelox, and Tribulus terrestris have promising evidence as herbal products, alongside l-arginine as a nutritional supplement, for ED based on IIEF outcomes, but need further exploration. Another meta-analysis of 2 trials on the efficacy of aspirin on erectile function in men with vasculogenic ED reported a significant improvement in erectile function with aspirin (mean difference: 5.14, 95 % CI [3.89, 6.40], and I² = 0 %). However, aspirin caused adverse events, and the overall quality of the evidence was moderate. Although vasodilators like sildenafil and tadalafil are widely used, they are associated with their share of adverse effects and a long list of contraindications. Hence, there is a dire need for a safe remedy to improve sexual function in both men and women.

Lack of sleep can lead to multiple disease conditions in an individual, and stress, anxiety, and sleep have an unavoidable relationship. Salve J. et al. (2019) reported a significant reduction in the PSS scores with Ashwagandha 250 mg/day (p < 0.05) and 600 mg/day (p < 0.001) [13]. Compared to the placebo group participants, the participants receiving Ashwagandha had a significant improvement in sleep quality. Stress is one of the most common causes of subpar sexual performance and diminishing sex drive. Stress adversely affects sexual function. As an adaptogen, Ashwagandha significantly helps to manage stress by reducing the concentration of stress hormones in the blood. Thus, this stress-managing effect of Ashwagandha makes a direct contribution to sexual health. Additionally, ARE enhances overall energy, stamina, and endurance. Stress can interfere with sexual function and cause ED [32]. Thus, the ashwagandha herb might initially aid in lowering stress levels. In our study, we also observed improvements in QOL with ARE treatment, suggesting that Ashwagandha could potentially have benefits for stress and infertility.

The safety of ARE is established through various published clinical studies in humans [17,[33], [34], [35]]. Animal studies have also reported the safety of ARE for reproductive organs and fetuses. In a recent study, the No Observed Adverse Effect Level (NOAEL) of ARE was 2000 mg/kg body weight/day in rats after repeated oral administration for 90 days (Kalaivani et al., 2023) [34]. Langade D. et al. (2023) [35] reported that with 28-day repeated dose administration, ARE does not show any major abnormality in rats with doses up to 5 times the recommended human dose. These findings substantiate the safety of ashwagandha root extract.

The findings from current study indicate that ARE may offer clinically meaningful benefits in improving sexual desire, orgasmic function, sperm parameters, and overall quality of life in men, with a favorable safety profile. These results suggest that ARE could be a valuable adjunctive treatment for men seeking improvements in sexual health and fertility, particularly in those with mild sexual dysfunction or fertility concerns. The lack of adverse events further enhances its potential as a safe, natural alternative for these purposes. However, further studies with larger sample sizes and long-term follow-up would be needed to confirm these findings and better understand the sustained effects of ARE. It boasts a historical legacy of enhancing sexual health, spanning thousands of years. Furthermore, ashwagandha's capacity to enhance neuromuscular endurance, mental and physical resilience, and tissue viability makes it a recommended complementary treatment in various psychosomatic disorders.

4.1. Strengths and limitations

The age, lifestyle factors, health conditions, could have impacted the results, but the stringent study inclusion criteria employed in the study were designed to mitigate their impact. The strengths of this study include its double-blind design and use of validated outcome measures. Beyond its myriad other benefits, the limitations of the study were the relatively small sample in a controlled environment with the inclusion of healthy men. Although the validated scales were used in the study, the patient-reported scales include various aspects of health, functioning, or well-being from their perspective. Thus, other limitation is the potential for patient-reported bias, which can lead to inaccurate results. This bias may arise due to factors such as social desirability, memory recall issues, or the patient's personal interpretation of questions. Additionally, the diversity of findings among different individuals can also contribute to variability in the results, making it challenging to draw consistent conclusions across the study population.

5. Conclusion

The study observed noteworthy enhancements in the sexual activity scores and semen parameters with 8-week oral administration of Ashwagandha root extract in healthy men visiting the infertility center. Furthermore, a substantial improvement has been observed in the scores of both the SDI-2 and the IIEF, specifically for orgasmic function (OF) and sexual desire (SD) domains, and satisfaction with sexual activity. Ashwagandha root extract was well tolerated with no adverse events reported by the participants, and no changes in hepatic and renal parameters in blood. The real-world scenario may differ from the controlled study environment. A lack of awareness and education about sexual activity and health among many participants could have influenced the results. Future research based on this study could be conducted in real-world settings to validate these findings in larger and more diverse populations. Additionally, exploring the correlation between stress and its impact on various aspects of sexual health would be a valuable direction for future studies.

Ethical approval

The ethical approval was taken from Institutional Ethics Committee (DYP/IEC/14/2022; dt. 26-08-2022). The study was registered with the clinical trials registry of India [# CTRI/2022/09/045646; dt: 19/09/2022)

Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial, or non-profit sectors.

Data availability

Data will be made available based on request.

Author contribution

AM: Study planning, clinical assessments, data collection, manuscript review, resources, supervision SM: Clinical assessments, data collection, manuscript preparation, resources, supervision AT: Clinical assessments, data collection, resources, supervision AB: Clinical assessments, data collection, manuscript preparation, resources, supervision AM: Clinical assessments, data collection, resources, supervision DL: Study planning, data analysis, manuscript review.

Declaration of generative AI in scientific writing

During the preparation of this work the authors used QuillBot to improve the language. After using this tool/service, the authors reviewed and edited the content as needed and takes full responsibility for the content of the publication.

Conflict of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.