Efficacy and safety of Ashwagandha Root Extract on Sexual Health in Healthy Women: Findings of a Prospective, Randomized, Double-Blind, Placebo-Controlled Study

doi:10.21203/rs.3.rs-5268403/v1

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Efficacy and safety of Ashwagandha Root Extract on Sexual Health in Healthy Women: Findings of a Prospective, Randomized, Double-Blind, Placebo-Controlled Study

https://doi.org/10.21203/rs.3.rs-5268403/v1

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Background: Ashwagandha is an herbal extract known for its potential benefits on various aspects of human health, including stress reduction and hormone regulation.

Objective: This prospective, randomized, double-blind, placebo-controlled study investigated the role of Ashwagandha Root Extract (ARE) in enhancing sexual function in healthy women with Female Sexual Dysfunction (FSD).

Materials and Methods: Sixty-two healthy women aged 18-50 years were randomly assigned to receive Ashwagandha root extract (ARE) 600mg/d (n=31), or identical placebo (n=31) for 8 weeks. Study assessments were done at baseline, week 2, week 4, and week 8. The primary outcome was Female Sexual Function Index (FSFI) scores, whereas secondary outcomes were Female Sexual Distress Scale (FSDS-R), Satisfying Sexual Encounters (SSEs), Perceived Stress Scale (PSS-10), and Quality of Life (SF-12 QoL) assessed at all visits. Laboratory assessments included serum sex hormones (Follicle-Stimulating Hormone (FSH), Luteinizing Hormone (LH), Progesterone, Estrogen- E2, Prolactin, and Testosterone), liver enzymes and renal parameters estimated at baseline and week 8.

Results: One patient was lost to follow-up and data of 61 (31 ARE, 30 placebo) patients was included for efficacy analysis. ARE significantly improved the mean (SD) FSFI total scores from 51.65 (10.23) at baseline to 71.94 (10.33) at week 8 as compared to placebo 51.77 (9.68) and 61.83 (8.38) baseline and week 8 respectively (p=0.002). This improvement was observed in ‘desire’ and ‘sexual satisfaction’ domains of FSFI scale. Similarly, assessments of sexual activity (SSE) shows greater improvements with ARE in ‘satisfying sexual events’ and ‘sexual desire’ (p<0.0001). The scores for PSS (p=0.0009), and SF-12 (p=0.044) were better with ARE compared to placebo at week 8. No significant changes or abnormalities were observed for hormones. Only one woman with placebo reported mild dizziness.

Conclusion: Ashwagandha root extract holds promise as a safe and effective option for improving sexual health in women.

Sexual & Reproductive Medicine

Female Sexual Dysfunction

Ashwagandha

SSE

FSDS-R

FSFI

PSS-10

SF-12

Female Sexual Dysfunction (FSD) is very common in all age groups and can take the form of Female Sexual Arousal Disorder (FSAD) or Female Orgasmic Disorder (FOD). [1]Some women may experience genital and subjective arousal disorders or isolated genital sexual arousal disorders which can be associated with decreased libido, vaginal dryness, reduced genital perception, decreased arousal, pain during intercourse, and difficulty achieving orgasm.[2] [3] [4] FSD affects around 40% of women and is more common with advancing age, and therapeutic options are limited. [5]

Ashwagandha [Withania somnifera], also called Indian Winter cherry or Indian Ginseng, is an adaptogenic herb used in Ayurveda, the traditional Indian medical system.[6] Ashwagandha has been reported to lower cortisol levels in chronic stress, restore adrenal function, and balance the sympathetic nervous system. [7] [8] For centuries, it has been utilized as a ‘Rasayana’ and recognized for its various health benefits.[9] As a Rasayana herb, it is an anti-stress agent, improving brain function, memory, and reproductive balance while enhancing the body's resilience to stress and promoting cell-mediated immunity.[10] The root of Ashwagandha has proven to effectively reduce stress hormones in the blood, leading to improved sexual health, enhanced energy levels, and better stamina and endurance. [11] Grown in India, Ashwagandha is highly valued for its adaptogenic properties, which energize, rejuvenate, and revitalize the body. Additionally, it boasts potent antioxidant properties that protect the body from cellular damage caused by free radicals.[12] [13]Ashwagandha extract is a useful therapeutic agent due to the presence of numerous phytochemicals.[13] [14] [15]Animal studies have also confirmed that Ashwagandha can affect sex hormone production by regulating luteinizing hormone, follicle-stimulating hormone, testosterone, and progesterone.[16] [17] [18] Moreover, ARE is thought to help reduce female sexual dysfunction by counteracting androgen deficiency syndrome, which can cause a lack of sexual desire in some women.[19] [20] This study aimed to test the effectiveness of ARE on enhancing sexual health in healthy women.

Study design

This 8-week prospective, randomized, double-blind, placebo-controlled clinical study was conducted to evaluate the efficacy and safety of ashwagandha root extract on sexual health in healthy women. The study (Clinical trial registration no. CTRI/2022/09/045890; dt. 27-09-2022) was compliant with the ICH GCP E6 R2 2016, Guidance for Good Clinical Practices (GCP), New Drugs and Clinical Trials 2019 (India), and Declaration of Helsinki (Taipei 2016). The study sites and study related documents were reviewed and approved by the Institutional Ethics Committee (DYP/IEC/15/2022; dt. 26-08-2022). Written informed consent was obtained in preferable languages (Hindi, Marathi, English) from all participants prior to the enrolment.

Study participants

The study sample consisted of 92 married or unmarried healthy women between 18 to 50 years of age visiting the study sites for seeking interventions for their sexual problems. Women who met the inclusion and exclusion criteria were enrolled in the study with baseline scores of 11–26 on the FSFI and FSDS-R scales, and in a stable, monogamous, heterosexual relationships with partners were enrolled. 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 were included. The study expected women participants to attempt sexual intercourse at least four or more times monthly. Women with any acute illness, those with a clinically significant medical history, or conditions that could jeopardize safety or study validity were not enrolled.

Interventions

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

Sample size

The sample size required for the study was calculated based on previously reported findings on the effects of ashwagandha over eight weeks on reducing FSDS-R. With 35 participants in each group, a total of 70 participants were deemed necessary to achieve 80% power in detecting a difference of 3.74 for the change in FSDS-R total score after eight weeks between the ARE and Placebo, using a one-sided two-sample t-test with a significance level (alpha) of 2.5%. The sample size accounted for the 10% expected loss to follow-up. [17]

Randomization and blinding

Study participants were randomly assigned to ARE or identical placebo in a 1:1 randomization ratio. Randomization was performed using a computer-generated pre-determined randomization list. The investigator received the randomization codes in separate envelopes for each study participant and was instructed to open the envelope only after assigning the study number to the eligible participant.

Primary outcome

The primary outcome of the study was a mean change in FSFI score from baseline to the end of four and eight weeks. FSFI survey consists of 19 questions that evaluate a woman's sexual performance across six different domains - sexual desire, arousal, lubrication, orgasm, satisfaction, and pain.[21] Each domain's score was calculated by adding up the scores of its questions and multiplying them by a correction factor. The minimum score for each domain is 6, and the maximum total score is 36.

Secondary outcomes

The secondary outcomes of the study were mean change in SSEs, FSDS-R score, serum hormones (Estrogen-E2, Progesterone, FSH, LH, Prolactin, and Testosterone), PSS-10-10 score and SF-12 scores from baseline visit to end of four and eight weeks. SSE was assessed through a structured survey where women were instructed to provide record of their sexual activities like, number of intercourse and non-intercourse sexual events, the occurrence of orgasms, the level of sexual desire, and the satisfaction. Women were also requested to provide a score indicating the intensity of their sexual desire within the last 24 hours or since their previous assessment. The FSDS-R and FSDS-R are highly reliable instruments to measure personal distress related to sexuality in women.[22] The FSDS-R with 7-day recall is particularly effective, demonstrating good discriminant validity and high internal consistency to measure personal distress in women with poor sexual function. [23] The PSS-10 instrument is the most utilized tool for measuring stress perception. It assesses the extent to which one perceives situations in one's life as stressful.[24] Serum hormones estimated were estrogen-E2, progesterone, testosterone, FSH, LH and prolactin using chemiluminescent immunoassay (CMIA) at baseline and week 8. The lab data (hepatic parameters) were included to assess the safety of ARE. Thus, the clinical safety assessment was based upon the frequency of these reported events.

Statistical Analysis

Statistical Package (Stata IC 13.1, Stata Corp, USA) version 25.0 was utilized for statistical analyses. Group comparison (ARE group versus placebo group) of demographic baseline characteristics scores was conducted using an independent t-test. To evaluate the potential changes in FSFI, SSEs and FSDS-R, PSS-10, SF-12, hormone levels, and biochemical and hematological parameters between ARE and placebo groups, a two-way analysis of variance (ANOVA) with Bonferroni post hoc corrections was performed. Wherever applicable, 95% confidence intervals (C.I.) have been considered. The results were presented as mean ± SD, and significance was considered at p < 0.05.

Demographics

Table 1 shows the demographic and baseline information for all participants in the intent-to-treat dataset.

Table 1

Demography and baseline assessments for all parameters for participants enrolled in the ITT dataset.
	ARE (n\(\:=31\))	Placebo (n\(\:=31\))
	Mean (SD)	Mean (SD)	p*
Age (years)	28.35 (6.83)	30.13 (7.71)	0.341
BMI (kg/m2)	24.60 (4.43)	25.55 (2.73)	0.314
SBP (mmHg)	118.74 (3.43)	117.74 (4.52)	0.330
DBP (mmHg)	79.77 (3.41)	79.42 (5.62)	0.765
Pulse rate (per min)	72.68 (4.38)	71.65 (2.76)	0.272
FSFI scale
▪ Desire	5.45 (1.77)	5.42 (0.96)	0.929
▪ Arousal	10.19 (3.04)	10.26 (2.14)	0.923
▪ Lubrication	11.71 (2.91)	11.29 (2.45)	0.542
▪ Orgasm	11.29 (2.45)	8.26 (2.63)	0.960
▪ Satisfaction	9.03 (2.11)	9.10 (2.01)	0.902
▪ Pain	7.00 (2.29)	7.19 (3.09)	0.781
▪ Total FSFI Score	51.65 (10.23)	51.55 (9.59)	0.969
FSDS
▪ FSDS score	16.71 (8.15)	16.74 (4.56)	0.985
PSS
▪ PSS Score	18.23 (1.98)	18.19 (2.94)	0.960
SF-12
▪ SF-12 Score	30.52 (3.64)	30.26 (4.94)	0.816
SSE
▪ No. of intercourse	2.03 (4.48)	1.94 (2.58)	0.917
▪ No. of non-sexual events	4.06 (7.68)	4.00 (9.66)	0.977
▪ No. of orgasms	0.81 (1.51)	1.10 (1.70)	0.481
▪ No. of satisfying sexual activity	0.90 (1.87)	1.00 (1.59)	0.827
▪ Level of sexual desire	1.55 (0.77)	1.87 (0.67)	0.083
Hormones (serum)
▪ Estrogen-E₂ (ng/mg)	73.30 (42.64)	73.82 (52.19)	0.966
▪ Progesterone (ng/mL)	12.69 (40.72)	13.73 (23.74)	0.902
▪ FSH (mIU/mL)	10.36 (14.73)	10.94 (14.63)	0.878
▪ LH (mIU/mL)	8.82 (10.18)	8.82 (9.32)	0.999
▪ Prolactin (ng/mL)	19.13 (11.04)	18.89 (6.49)	0.919
▪ Testosterone (ng/mL)	32.12 (16.90)	29.40 (13.85)	0.491
^*p-value was obtained using an independent two‐sample t‐test for differences between two means (two‐tailed).
ARE: Ashwagandha root extract; BMI: Body mass index; DBP: Diastolic blood pressure; ITT: intent-to-treat; SBP: Systolic blood pressure; SSE: Satisfying Sexual Events ; FSDS:Female Sexual Distress Scale ; FSFI: Female Sexual Function Index; FSH: Follicle-Stimulating Hormone; LH: Luteinizing Hormone; PSS: ; SF-12: Short form 12.

Primary outcome: FSFI

Table 2 displays the data for total FSFI scores in two groups at all time points. The increase in the FSFI total score was significantly higher (p < 0.002) in the ARE group than in the placebo group at week 8. There was greater increase (p < 0.003) in the scores for desire domain of FSFI from baseline to week 8 with ARE. The mean increase in arousal domain scores of FSFI from baseline to week 8 were significantly higher in ARE (p < 0.007) as compared to placebo. For the lubrication domain score, the effects were also strong, with the ARE group having greater improvement, relative to the placebo, at week 4 (p = 0.006) and at week 8 (p = 0.036). ARE significantly reduced pain compared to placebo at week 2 (p = 0.020), week 4 (p = 0.050), and week 8 (p = 0.035). Arousal and lubrication improved more with ARE (p = 0.002) than with placebo, leading to an overall improvement.

Table 2

Comparison of FSFI, FSDS-R, PSS, and SF-12 scale scores at baseline and during the study period in the PP dataset.
			Baseline	Week 2	Week 4	Week 8
		N	Mean (SD)	Mean (SD)	Mean (SD)	Mean (SD)	p*
FSFI
Desire	ARE	31	5.45 (1.77)	7.03 (0.95)	7.29 (1.01)	8.00 (1.18)	0.003
Desire	Placebo	30	5.40 (0.97)	5.77 (1.30)	5.93 (1.23)	6.20 (1.99)	0.003
Arousal	ARE	31	10.19 (3.04)	12.97 (1.66)	14.26 (2.34)	14.29 (2.60)	0.056
Arousal	Placebo	30	10.33 (2.14)	12.13 (1.70)	12.23 (3.04)	12.53 (2.30)	0.056
Lubrication	ARE	31	11.71 (2.91)	14.00 (2.10)	14.81 (2.21)	14.48 (3.25)	0.390
Lubrication	Placebo	30	11.23 (2.47)	12.03 (2.80)	12.87 (3.01)	12.53 (3.82)	0.390
Orgasm	ARE	31	8.26 (2.63)	9.81 (1.96)	10.90 (1.80)	12.16 (1.90)	0.064
Orgasm	Placebo	30	8.27 (2.48)	8.63 (2.24)	8.77 (2.45)	10.47 (2.79)	0.064
Satisfaction	ARE	31	9.03 (2.11)	10.77 (1.23)	11.45 (1.59)	11.87 (1.86)	0.027
Satisfaction	Placebo	30	9.10 (2.04)	9.50 (2.19)	9.30 (2.42)	10.63 (2.53)	0.027
Pain	ARE	31	7.00 (2.29)	10.23 (1.86)	10.42 (2.14)	11.13 (2.63)	0.108
Pain	Placebo	30	7.43 (2.84)	8.83 (2.65)	9.17 (2.72)	9.47 (3.35)	0.108
Total score	ARE	31	51.65 (10.23)	64.81 (5.63)	69.13 (8.69)	71.94 (10.33)	0.002
Total score	Placebo	30	51.77 (9.68)	56.90 (7.90)	58.27 (8.14)	61.83 (8.38)	0.002
FSDS - R	ARE	31	16.71 (8.15)	9.06 (6.13)	7.26 (3.71)	6.81 (3.23)	0.255
FSDS - R	Placebo	30	16.93 (4.51)	12.03 (8.42)	11.70 (7.73)	10.60 (5.54)	0.255
PSS − 10	ARE	31	18.23 (1.98)	12.35 (3.92)	11.84 (2.34)	11.32 (2.63)	0.001
PSS − 10	Placebo	30	18.23 (2.98)	15.73 (3.39)	15.63 (3.57)	15.30 (3.31)	0.001
SF-12	ARE	31	30.52 (3.64)	32.97 (3.15)	33.68 (2.91)	35.39 (3.77)	0.044
SF-12	Placebo	30	30.17 (5.00)	30.73 (2.56)	31.10 (2.96)	31.33 (4.25)	0.044
FSFI: female sexual function index; PP: per-protocol. ^*p-value was obtained using a two-way ANOVA test with Bonferroni post-hoc corrections (α > 0.05). FSDS: Female Sexual Distress Scale; PSS: Perceived Stress Scale; SF-12: Short Form Survey.

There is consistent and robust improvement seen within the ARE group, showcasing significant shifts at weeks 2, 4, and 8, compared to the corresponding values for the placebo respectively.

Secondary outcome measures

SSEs

The level of sexual desire with the ARE group (p < 0.0001) was consistently higher levels than the placebo group throughout the study period. No significant differences were found in the number of intercourse (p = 0.628) or non-sexual events (p = 0.457) between the two groups throughout the study period. The mean change from baseline in all SSE domain scores was higher in the ARE group compared to the placebo group (Fig. 1).

FSDS-R, PSS-10, and SF-12

Table 2 shows the FSDS-R, PSS-10, and SF-12 scores in two groups. Difference in FSDS-R scores between the two groups was not statistically significant (p > 0.05). There was a decrease in PSS-10 score for ARE group 11.32 (2.63) and placebo group 15.30 (3.31) at Week 8. The difference in PSS-10 scores (p = 0.0009), between the two groups was statistically significant, indicating a meaningful impact of the ARE on perceived stress. Moreover, during the study, the SF-12 quality of life scores consistently increased in ARE group, reaching 35.39 (3.77) at Week 8, while the scores showed modest rise, ending at 31.33 (4.25) at the same time point in the placebo group. The difference in SF-12 scores between the two groups was statistically significant (p = 0.044). The ARE group demonstrated a mean change in FSDS-R scores from (-7.65) at week 2, (-9.45) at week and (-9.9) at week 8, while the placebo group demonstrated mean changes of (-4.9) at week 2 and (-6.33) at week 8.

Hormonal assessment

Table 3 shows measured levels of serum hormones. The levels of the hormones FSH and LH were determined by Electrochemiluminescence Immunoassay (ECLIA), whereas the levels of the hormones Estrogen-E2, Progesterone, and Testosterone were determined using Chemiluminescence Immunoassay (CLIA). No significant differences were observed in serum hormone levels between the two groups at either time point (p > 0.05 for all).

Table 3

Serum hormonal levels at baseline and week 8 in the PP dataset.
Hormone	Groups	Mean (SD)
Hormone	Groups	Baseline	Week 8	p*
Estrogen (pg/ml)	ARE (n = 31)	73.30 (42.64)	74.89 (41.09)	0.865
Estrogen (pg/ml)	Placebo (n = 30)	74.88 (52.75)	73.50 (55.33)	0.865
Progesterone (ng/ml)	ARE (n = 31)	12.69 (40.72)	14.05 (41.81)	0.739
Progesterone (ng/ml)	Placebo (n = 30)	13.86 (24.14)	11.32 (12.06)	0.739
FSH (mIU/ml)	ARE (n = 31)	10.36 (14.73)	8.42 (11.50)	0.947
FSH (mIU/ml)	Placebo (n = 30)	11.10 (14.85)	9.49 (13.64)	0.947
LH (IU/L)	ARE (n = 31)	8.82 (10.18)	10.54 (9.02)	0.972
LH (IU/L)	Placebo (n = 30)	8.91 (9.46)	10.51 (8.96)	0.972
Prolactin (ng/dL)	ARE (n = 31)	19.13 (11.04)	22.97 (12.88)	0.753
Prolactin (ng/dL)	Placebo (n = 30)	19.23 (6.32)	21.87 (10.58)	0.753
Testosterone (ng/dL)	ARE (n = 31)	32.12 (16.90)	34.07 (15.55)	0.903
Testosterone (ng/dL)	Placebo (n = 30)	29.97 (13.71)	31.27 (12.31)	0.903
FSH: Follicle-stimulating hormone; LH: Luteinizing hormone; PP: per-protocol. ^*p-value was obtained using a two-way ANOVA test with Bonferroni post-hoc corrections.

Table 4

Hematological and biochemical at baseline and week 8.
						t-test		Difference		95% C.I. of the Difference		Effect size	95% C.I.
	Treatment	N	Mean	SD	SE	t	p	Mean	SE	Lower	Upper	Cohen's d	Lower	Upper
Baseline
Hb (gm/dL)	ARE	31	9.91	1.35	0.24	0.259	0.797	0.10	0.37	-0.65	0.84	0.066	-0.44	0.57
	Placebo	30	9.82	1.55	0.28
Creatinine (gm/dL)	ARE	31	0.82	0.23	0.04	2.284	0.026	0.13	0.06	0.02	0.25	0.585	0.07	1.10
	Placebo	30	0.69	0.22	0.04
BUN (IU/L)	ARE	31	18.91	1.35	0.24	0.259	0.797	0.10	0.37	-0.65	0.84	0.066	-0.44	0.57
	Placebo	30	18.82	1.55	0.28
Bilirubin Total (mg/dL)	ARE	31	0.70	0.21	0.04	0.910	0.367	0.05	0.05	-0.06	0.15	0.233	-0.27	0.74
	Placebo	30	0.66	0.19	0.03
Bilirubin Direct (mg/dL)	ARE	31	0.24	0.17	0.03	0.566	0.573	0.02	0.04	-0.06	0.10	0.145	-0.36	0.65
	Placebo	30	0.21	0.14	0.03
Protein (gm/dL)	ARE	31	7.60	1.11	0.20	-0.212	0.833	-0.06	0.27	-0.60	0.48	-0.054	-0.56	0.45
	Placebo	30	7.66	0.99	0.18
Albumin (gm/dL)	ARE	31	4.62	0.58	0.10	-0.258	0.798	-0.04	0.14	-0.32	0.24	-0.066	-0.57	0.44
	Placebo	30	4.66	0.51	0.09
Globulin (gm/dL)	ARE	31	2.98	0.54	0.10	-0.162	0.872	-0.02	0.13	-0.28	0.24	-0.041	-0.54	0.46
	Placebo	30	3.00	0.49	0.09
A-G Ratio	ARE	31	1.57	0.10	0.02	0.038	0.970	0.00	0.03	-0.05	0.05	0.010	-0.49	0.51
	Placebo	30	1.57	0.10	0.02
ALT (IU/L)	ARE	31	29.71	1.35	0.24	0.259	0.797	0.10	0.37	-0.65	0.84	0.066	-0.44	0.57
	Placebo	30	29.62	1.55	0.28
AST (IU/L)	ARE	31	29.91	1.35	0.24	0.259	0.797	0.10	0.37	-0.65	0.84	0.066	-0.44	0.57
	Placebo	30	29.82	1.55	0.28
ALP (IU/L)	ARE	31	89.14	4.06	0.73	0.259	0.797	0.29	1.12	-1.94	2.52	0.066	-0.44	0.57
	Placebo	30	88.85	4.64	0.85
Week 8
Hb (gm/dL)	ARE	31	10.09	1.30	0.23	0.459	0.648	0.17	0.36	-0.56	0.89	0.118	-0.39	0.62
	Placebo	30	9.93	1.53	0.28
Creatinine (gm/dL)	ARE	31	1.75	1.67	0.30	-0.453	0.652	-0.19	0.42	-1.03	0.65	-0.116	-0.62	0.39
	Placebo	30	1.94	1.61	0.29
BUN (IU/L)	ARE	31	19.85	2.13	0.38	-0.426	0.672	-0.25	0.59	-1.43	0.93	-0.109	-0.61	0.39
	Placebo	30	20.10	2.48	0.45
Change at Week 8
Hb (gm/dL)	ARE	31	0.18	0.36	0.07	0.855	0.396	0.07	0.08	-0.09	0.24	0.219	-0.29	0.72
	Placebo	30	0.11	0.27	0.05
Creatinine (gm/dL)	ARE	31	0.93	1.52	0.27	-0.808	0.423	-0.32	0.40	-1.12	0.47	-0.207	-0.71	0.30
	Placebo	30	1.25	1.58	0.29
BUN (IU/L)	ARE	31	0.93	1.52	0.27	-0.869	0.388	-0.35	0.40	-1.15	0.45	-0.222	-0.73	0.28
	Placebo	30	1.28	1.61	0.29
Baseline
Bilirubin Total (mg/dL)	ARE	31	0.70	0.21	0.04	0.910	0.367	0.05	0.05	-0.06	0.15	0.233	-0.27	0.74
	Placebo	30	0.66	0.19	0.03
Bilirubin Direct (mg/dL)	ARE	31	0.24	0.17	0.03	0.566	0.573	0.02	0.04	-0.06	0.10	0.145	-0.36	0.65
	Placebo	30	0.21	0.14	0.03
Protein (gm/dL)	ARE	31	7.60	1.11	0.20	-0.212	0.833	-0.06	0.27	-0.60	0.48	-0.054	-0.56	0.45
	Placebo	30	7.66	0.99	0.18
Albumin (gm/dL)	ARE	31	4.62	0.58	0.10	-0.258	0.798	-0.04	0.14	-0.32	0.24	-0.066	-0.57	0.44
	Placebo	30	4.66	0.51	0.09
Globulin (gm/dL)	ARE	31	2.98	0.54	0.10	-0.162	0.872	-0.02	0.13	-0.28	0.24	-0.041	-0.54	0.46
	Placebo	30	3.00	0.49	0.09
A-G Ratio	ARE	31	1.57	0.10	0.02	0.038	0.970	0.00	0.03	-0.05	0.05	0.010	-0.49	0.51
	Placebo	30	1.57	0.10	0.02
ALT (IU/L)	ARE	31	29.71	1.35	0.24	0.259	0.797	0.10	0.37	-0.65	0.84	0.066	-0.44	0.57
	Placebo	30	29.62	1.55	0.28
AST (IU/L)	ARE	31	29.91	1.35	0.24	0.259	0.797	0.10	0.37	-0.65	0.84	0.066	-0.44	0.57
	Placebo	30	29.82	1.55	0.28
ALP (IU/L)	ARE	31	89.14	4.06	0.73	0.259	0.797	0.29	1.12	-1.94	2.52	0.066	-0.44	0.57
	Placebo	30	88.85	4.64	0.85
Week 8
Bilirubin Total (mg/dL)	ARE	31	0.67	0.28	0.05	0.398	0.692	0.02	0.06	-0.10	0.15	0.102	-0.40	0.60
	Placebo	30	0.64	0.19	0.04
Bilirubin Direct (mg/dL)	ARE	31	0.21	0.17	0.03	-1.203	0.234	-0.05	0.04	-0.12	0.03	-0.308	-0.81	0.20
	Placebo	30	0.25	0.12	0.02
Protein (gm/dL)	ARE	31	7.38	0.95	0.17	-0.576	0.567	-0.14	0.23	-0.61	0.33	-0.148	-0.65	0.36
	Placebo	30	7.51	0.88	0.16
Albumin (gm/dL)	ARE	31	4.45	0.45	0.08	-0.753	0.455	-0.08	0.11	-0.31	0.14	-0.193	-0.70	0.31
	Placebo	30	4.54	0.42	0.08
Globulin (gm/dL)	ARE	31	2.92	0.51	0.09	-0.407	0.685	-0.05	0.13	-0.30	0.20	-0.104	-0.61	0.40
	Placebo	30	2.97	0.48	0.09
A-G Ratio	ARE	31	1.55	0.13	0.02	0.014	0.989	0.00	0.03	-0.07	0.07	0.004	-0.50	0.51
	Placebo	30	1.55	0.14	0.03
ALT (IU/L)	ARE	31	30.65	2.13	0.38	-0.436	0.664	-0.26	0.59	-1.44	0.93	-0.112	-0.61	0.39
	Placebo	30	30.90	2.49	0.45
AST (IU/L)	ARE	31	30.85	2.13	0.38	-0.436	0.664	-0.26	0.59	-1.44	0.93	-0.112	-0.61	0.39
	Placebo	30	31.10	2.49	0.45
ALP (IU/L)	ARE	31	90.07	4.47	0.80	-0.053	0.958	-0.07	1.25	-2.56	2.43	-0.013	-0.52	0.49
	Placebo	30	90.14	5.27	0.96
Change at Week 8
Bilirubin Total (mg/dL)	ARE	31	-0.04	0.10	0.02	-0.883	0.381	-0.02	0.03	-0.07	0.03	-0.226	-0.73	0.28
	Placebo	30	-0.01	0.10	0.02
Bilirubin Direct (mg/dL)	ARE	31	-0.03	0.04	0.01	-4.484	< 0.001	-0.07	0.02	-0.10	-0.04	-1.148	-1.69	-0.60
	Placebo	30	0.04	0.07	0.01
Protein (gm/dL)	ARE	31	-0.22	0.28	0.05	-1.004	0.319	-0.08	0.08	-0.23	0.08	-0.257	-0.76	0.25
	Placebo	30	-0.14	0.33	0.06
Albumin (gm/dL)	ARE	31	-0.17	0.20	0.04	-0.882	0.381	-0.05	0.05	-0.16	0.06	-0.226	-0.73	0.28
	Placebo	30	-0.12	0.22	0.04
Globulin (gm/dL)	ARE	31	-0.05	0.10	0.02	-1.039	0.303	-0.03	0.03	-0.09	0.03	-0.266	-0.77	0.24
	Placebo	30	-0.02	0.13	0.02
A-G Ratio	ARE	31	-0.03	0.05	0.01	-0.147	0.884	0.00	0.01	-0.03	0.02	-0.038	-0.54	0.46
	Placebo	30	-0.02	0.05	0.01
ALT (IU/L)	ARE	31	0.93	1.52	0.27	-0.883	0.381	-0.35	0.40	-1.16	0.45	-0.226	-0.73	0.28
	Placebo	30	1.29	1.61	0.29
AST (IU/L)	ARE	31	0.93	1.52	0.27	-0.883	0.381	-0.35	0.40	-1.16	0.45	-0.226	-0.73	0.28
	Placebo	30	1.29	1.61	0.29
ALP (IU/L)	ARE	31	0.93	1.52	0.27	-0.883	0.381	-0.35	0.40	-1.16	0.45	-0.226	-0.73	0.28
	Placebo	30	1.29	1.61	0.29
ARE: Ashwagandha, BMI: Body mass index, C.I.: Confidence Interval, SEM: Standard error for mean, SD: Standard deviation, AST: Aspartate aminotransferase, ALT: Alanine transaminase, ALP: Alkaline Phosphatase, BUN: Urea/Blood Urea Nitrogen, C.I.: Confidence Interval, CK: Creatinine Kinase, CRP:C-reactive protein, RBC: Red blood cell, PCV: Hematocrit, SEM: Standard error for mean, SD: Standard deviation

Table 5

FSFI scores in the PP dataset.
	Treatment					t-test		Difference		95% C.I. of the Difference		Effect size	95% C.I.
		N	Mean	SD	SE	t	p	Mean	SE	Lower	Upper	Cohen's d	Lower	Upper
Baseline
FSFI (Desire)	ARE	31	5.45	1.77	0.32	0.141	0.889	0.05	0.37	-0.68	0.79	0.04	-0.47	0.54
	Placebo	30	5.40	0.97	0.18
FSFI (Arousal)	ARE	31	10.19	3.04	0.55	-0.207	0.837	-0.14	0.67	-1.49	1.21	-0.05	-0.55	0.45
	Placebo	30	10.33	2.14	0.39
FSFI (Lubrication)	ARE	31	11.71	2.91	0.52	0.688	0.494	0.48	0.69	-0.91	1.86	0.18	-0.33	0.68
	Placebo	30	11.23	2.47	0.45
FSFI (Orgasm)	ARE	31	8.26	2.63	0.47	-0.013	0.990	-0.01	0.65	-1.32	1.30	0.00	-0.51	0.50
	Placebo	30	8.27	2.48	0.45
FSFI (Satisfaction)	ARE	31	9.03	2.11	0.38	-0.128	0.899	-0.07	0.53	-1.13	0.99	-0.03	-0.53	0.47
	Placebo	30	9.10	2.04	0.37
FSFI (Pain)	ARE	31	7.00	2.29	0.41	-0.657	0.514	-0.43	0.66	-1.75	0.89	-0.17	-0.67	0.34
	Placebo	30	7.43	2.84	0.52
FSFI (Total)	ARE	31	51.65	10.23	1.84	-0.048	0.962	-0.12	2.55	-5.23	4.98	-0.01	-0.51	0.49
	Placebo	30	51.77	9.68	1.77
Change from baseline at 2 weeks
FSFI (Desire)	ARE	31	1.58	2.38	0.43	2.310	0.024	1.21	0.53	0.16	2.27	0.59	0.08	1.10
	Placebo	29	0.37	1.65	0.30
FSFI (Arousal)	ARE	31	2.77	3.23	0.58	1.271	0.209	0.97	0.77	-0.56	2.51	0.33	-0.18	0.83
	Placebo	29	1.80	2.72	0.50
FSFI (Lubrication)	ARE	31	2.29	3.11	0.56	1.774	0.081	1.49	0.84	-0.19	3.17	0.45	-0.06	0.96
	Placebo	29	0.80	3.45	0.63
FSFI (Orgasm)	ARE	31	1.55	2.26	0.41	1.692	0.096	1.18	0.70	-0.22	2.58	0.43	-0.08	0.94
	Placebo	29	0.37	3.13	0.57
FSFI (Satisfaction)	ARE	31	1.74	2.13	0.38	2.136	0.037	1.34	0.63	0.08	2.60	0.55	0.03	1.06
	Placebo	29	0.40	2.75	0.50
FSFI (Pain)	ARE	31	3.23	3.00	0.54	2.078	0.042	1.83	0.88	0.07	3.58	0.53	0.02	1.04
	Placebo	29	1.40	3.83	0.70
FSFI (Total)	ARE	31	13.16	11.13	2.00	2.887	0.005	8.03	2.78	2.46	13.59	0.74	0.22	1.26
	Placebo	29	5.13	10.57	1.93
Change from baseline at 4 weeks
FSFI (Desire)	ARE	31	1.84	2.03	0.37	2.858	0.006	1.31	0.46	0.39	2.22	0.73	0.21	1.25
	Placebo	30	0.53	1.48	0.27
FSFI (Arousal)	ARE	31	4.06	3.54	0.64	2.286	0.026	2.16	0.95	0.27	4.06	0.59	0.07	1.10
	Placebo	30	1.90	3.85	0.70
FSFI (Lubrication)	ARE	31	3.10	3.42	0.61	1.634	0.108	1.46	0.90	-0.33	3.26	0.42	-0.09	0.92
	Placebo	30	1.63	3.58	0.65
FSFI (Orgasm)	ARE	31	2.65	2.46	0.44	3.058	0.003	2.15	0.70	0.74	3.55	0.78	0.26	1.30
	Placebo	30	0.50	3.00	0.55
FSFI (Satisfaction)	ARE	31	2.42	2.13	0.38	3.506	0.001	2.22	0.63	0.95	3.49	0.90	0.37	1.42
	Placebo	30	0.20	2.78	0.51
FSFI (Pain)	ARE	31	3.42	3.21	0.58	1.855	0.069	1.69	0.91	-0.13	3.51	0.47	-0.04	0.98
	Placebo	30	1.73	3.87	0.71
FSFI (Total)	ARE	31	17.48	12.44	2.23	3.638	0.001	10.98	3.02	4.94	17.03	0.93	0.40	1.46
	Placebo	30	6.50	11.08	2.02
Change from baseline at 8 weeks
FSFI (Desire)	ARE	31	2.55	2.23	0.40	3.025	0.004	1.75	0.58	0.59	2.90	0.77	0.25	1.29
	Placebo	30	0.80	2.28	0.42
FSFI (Arousal)	ARE	31	4.10	3.40	0.61	2.157	0.035	1.90	0.88	0.14	3.66	0.55	0.04	1.06
	Placebo	30	2.20	3.47	0.63
FSFI (Lubrication)	ARE	31	2.77	4.26	0.76	1.444	0.154	1.47	1.02	-0.57	3.52	0.37	-0.14	0.87
	Placebo	30	1.30	3.69	0.67
FSFI (Orgasm)	ARE	31	3.90	3.00	0.54	2.272	0.027	1.70	0.75	0.20	3.20	0.58	0.07	1.09
	Placebo	30	2.20	2.85	0.52
FSFI (Satisfaction)	ARE	31	2.84	2.73	0.49	1.988	0.051	1.31	0.66	-0.01	2.62	0.51	0.00	1.02
	Placebo	30	1.53	2.37	0.43
FSFI (Pain)	ARE	31	4.13	3.04	0.55	2.233	0.029	2.10	0.94	0.22	3.97	0.57	0.06	1.08
	Placebo	30	2.03	4.21	0.77
FSFI (Total)	ARE	31	20.29	13.88	2.49	3.523	0.001	10.22	2.90	4.42	16.03	0.90	0.37	1.43
	Placebo	30	10.07	7.86	1.44
ARE: Ashwagandha; FSFI: female sexual function index; PP: per-protocol. ^*p-value was obtained using a two-way ANOVA test with Bonferroni post-hoc corrections (α > 0.05).

Table 6

SSE scores in PP dataset.
						t-test		Difference		95% C.I. of the Difference		Effect size	95% C.I.
	Treatment	N	Mean	SD	SE	t	p	Mean	SE	Lower	Upper	Cohen's ‘d’	Lower	Upper
Baseline
No. of intercourse	ARE	31	2.03	4.48	0.81	0.324	0.747	0.30	0.92	-1.55	2.14	0.08	-0.42	0.58
	Placebo	30	1.73	2.36	0.43
No. of non-sexual events	ARE	31	4.06	7.68	1.38	-0.001	0.999	0.00	2.25	-4.51	4.50	0.00	-0.50	0.50
	Placebo	30	4.07	9.82	1.79
No. of orgasms	ARE	31	0.81	1.51	0.27	-0.627	0.533	-0.26	0.41	-1.09	0.57	-0.16	-0.66	0.34
	Placebo	30	1.07	1.72	0.31
No. of satisfying sexual activity	ARE	31	0.90	1.87	0.34	0.086	0.932	0.04	0.43	-0.82	0.89	0.02	-0.48	0.52
	Placebo	30	0.87	1.43	0.26
Level of sexual desire	ARE	31	1.55	0.77	0.14	-1.564	0.123	-0.28	0.18	-0.65	0.08	-0.40	-0.91	0.11
	Placebo	30	1.83	0.65	0.12
2 weeks
No. of intercourse	ARE	31	5.03	3.20	0.57	1.389	0.170	0.87	0.62	-0.38	2.11	0.36	-0.15	0.86
	Placebo	30	4.17	1.21	0.22
No. of non-sexual events	ARE	31	4.94	4.88	0.88	0.514	0.609	1.00	1.95	-2.90	4.90	0.13	-0.37	0.63
	Placebo	30	3.93	9.65	1.76
No. of orgasms	ARE	31	4.19	2.26	0.41	0.270	0.788	0.13	0.47	-0.81	1.07	0.07	-0.43	0.57
	Placebo	30	4.07	1.26	0.23
No. of satisfying sexual activity	ARE	31	4.35	3.06	0.55	0.849	0.399	0.52	0.61	-0.71	1.75	0.22	-0.29	0.72
	Placebo	30	3.83	1.42	0.26
Level of sexual desire	ARE	31	2.32	0.48	0.09	6.010	0.000	0.86	0.14	0.57	1.14	1.54	0.96	2.11
	Placebo	30	1.47	0.63	0.11
4 weeks
No. of intercourse	ARE	31	7.90	13.35	2.40	1.293	0.201	3.17	2.45	-1.73	8.07	0.33	-0.18	0.84
	Placebo	30	4.73	1.36	0.25
No. of non-sexual events	ARE	31	6.48	5.31	0.95	1.092	0.279	2.15	1.97	-1.79	6.09	0.28	-0.23	0.78
	Placebo	30	4.33	9.54	1.74
No. of orgasms	ARE	31	4.77	1.50	0.27	0.674	0.503	0.27	0.41	-0.54	1.09	0.17	-0.33	0.67
	Placebo	30	4.50	1.68	0.31
No. of satisfying sexual activity	ARE	31	5.06	3.15	0.57	1.515	0.135	1.03	0.68	-0.33	2.39	0.39	-0.12	0.89
	Placebo	30	4.03	2.03	0.37
Level of sexual desire	ARE	31	2.19	0.60	0.11	1.715	0.092	0.26	0.15	-0.04	0.56	0.44	-0.07	0.95
	Placebo	30	1.93	0.58	0.11
8 weeks
No. of intercourse	ARE	31	9.16	9.76	1.75	0.890	0.377	1.66	1.87	-2.07	5.39	0.23	-0.28	0.73
	Placebo	30	7.50	3.07	0.56
No. of non-sexual events	ARE	31	7.19	5.15	0.92	1.408	0.164	2.79	1.98	-1.18	6.76	0.36	-0.15	0.87
	Placebo	30	4.40	9.73	1.78
No. of orgasms	ARE	31	6.35	3.19	0.57	0.124	0.902	0.09	0.71	-1.34	1.51	0.03	-0.47	0.53
	Placebo	30	6.27	2.29	0.42
No. of satisfying sexual activity	ARE	31	7.10	3.33	0.60	2.253	0.028	1.46	0.65	0.16	2.76	0.58	0.06	1.09
	Placebo	30	5.63	1.27	0.23
Level of sexual desire	ARE	31	2.45	0.62	0.11	2.229	0.030	0.35	0.16	0.04	0.67	0.57	0.06	1.08
	Placebo	30	2.10	0.61	0.11
SSE: Satisfying sexual events; ARE: Ashwagandha; C.I.: Confidence Interval; p-value was obtained using a two-way ANOVA test with Bonferroni post-hoc corrections (α > 0.05; SE: Standard Error.

Hematological and biochemical parameters

No significant differences emerged between the groups for most parameters (Hb, Creatinine, Protein, Albumin, Globulin, and A-G Ratio)

Safety assessment

The participants demonstrated good tolerance to the treatment, as evidenced by the occurrence of only one documented adverse event of dizziness with placebo, with no reports of any serious adverse events and no significant differences in laboratory parameters.

FSD is a prevalent and gradual condition that predominantly affects women. The symptoms include decreased libido, vaginal dryness, reduced genital sensitivity, diminished arousal, painful intercourse, and difficulties achieving orgasm. Currently, there are limited pharmacological options available for the treatment of FSD. Bumphenkiatikul T. et al. (2020) conducted a double-blind, randomized, placebo-controlled trial to investigate the effects of vaginal administration of conjugated estrogens tablet on sexual function in postmenopausal women with sexual dysfunction.[25] Estrogen failed to provide improvement in FSFI scores compared to placebo in each domain and overall index (p = 0.182). Anita H. Clayton et al. (2016) evaluated the efficacy/safety of bremelanotide (BMT), a melanocortin-receptor-4 agonist, to treat female sexual dysfunctions in premenopausal women.[26] Estrogen therapy should be opted for only when administered within a specific window of opportunity with an individualized approach. Unlike menopausal women who have estrogen replacement as a standard treatment, young women facing hormonal imbalances may not have similarly effective and safe therapeutic options available to them. This lack of alternatives underscores the importance of further research and development in this area to address the unique needs of this population. A meta-analysis of 11 studies reported a strong association between sexual dysfunction and infertility in women.[27] Authors also report that infertile women had problems with lubrication, orgasm, and satisfaction. Although a meta-analyses of 13 randomized clinical trials in 230 women with infertility and infertile couples (n = 512) reported benefit of counseling interventions to improve sexual satisfaction, the benefits of counseling depend on many factors and are questionable.[28]

Thus, there is a need for a safe and effective therapy to improve sexual drive and performance in women. This 8-week study compared the clinical efficacy and safety of ARE with an identical placebo in 62 healthy women. The findings of this study indicated that ARE significantly improved various aspects of sexual function, including reductions in pain, and improvement in FSFI, FSDS-R, PSS-10, and SF-12 scores with ARE compared to the placebo. Moreover, the treatment showed greater reduction in distress levels related to sexual problems and enhanced quality of life in terms of physical and mental well-being. The study highlighted the potential of ARE as an effective and safe alternative for women suffering from FSD. Ashwagandha use as a Rasayana herb has been associated with numerous health benefits, including enhanced brain and nervous system function, improved memory, and promotion of a healthy sexual and reproductive balance.[9] [13] Previous studies have reported the benefits of ashwagandha root extracts in treatment of both men and women with infertility.[11] [17]

Korean Red Ginseng (KRG) (Panax ginseng) in a dose 3 gm/day has been reported to improve sexual arousal and sexual life in 32 menopausal women in a placebo-controlled, double-blind, crossover clinical study.[29]This study used the Female Sexual Function Index and Global Assessment Questionnaire as assessment tools. The improvement in sexual arousal domain scores on FSFI was 4.16% with Korean red ginseng. We observed 40.23% improvement in scores for sexual arousal domain with Ashwagandha root extract (data not reported in results). Also, the dose used for Korean red ginseng was 3 gm/day, and there were two cases of vaginal bleeding that occurred with ginseng. One patient in our study also reported mild vaginal bleeding with placebo treatment which did not require any intervention.

Unlike studies done in the past which showed improvement for selected domains of SSE, our studies showed improvement in PSS-10 and level of sexual desire. In our study, the perceived stress scale (PSS-10) levels decreased (p < 0.001) from baseline values with ashwagandha extract by the end of 8 weeks. Previously stress-relieving properties of ashwagandha have been reported. Serum cortisol levels reduced with both Ashwagandha 250 mg/day (p < 0.05) and Ashwagandha 600 mg/day (p < 0.0001).[6]

This study had few limitations, including participants' limited awareness and education regarding sexual activity and sexual health. Additionally, the relatively short duration of our study, spanning eight weeks, may constrain the ability to draw conclusions about long-term benefits. Therefore, future research conducted in real-world settings with participants representing a broader range of backgrounds is warranted to provide a more comprehensive understanding of the topic. The study encouraged participants to engage in sexual intercourse at least four or more times monthly to capture relevant data, it did not mandate or coerce the participants to do so. This has limitations in the study's design as this may lead to potential bias. Nevertheless, our findings indicate that Ashwagandha root extract may serve as a beneficial intervention for improving sexual health among women in this demographic, and potentially among women more broadly.

Despite challenges highlighted by previous studies, our research contributes valuable insights into the potential of Ashwagandha root extract as a safe and effective alternative for women. Overall, this study contributes to the growing body of evidence supporting the use of Ashwagandha root extract in improving sexual health among women. No treatment related to adverse events was encountered, indicating that ARE is a safer alternative.

Author contributions

AM, SM, AT and DL contributed towards conception, study design, protocol development and manuscript review. AM and SM conducted the study and data collection. DL did the data analysis and manuscript writing.

Funding

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

Conflicts of interest

The authors have no conflict of interest.

Data availability

Data will be made based on request.

Acknowledgements

The authors thank Ixoreal BioMed Inc., Los Angeles, California, USA, for supplying the KSM- 66 ashwagandha root extract used in the study.

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The authors declare no competing interests.

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Efficacy and safety of Ashwagandha Root Extract on Sexual Health in Healthy Women: Findings of a Prospective, Randomized, Double-Blind, Placebo-Controlled Study

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Abstract

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Introduction

Materials and Methods

Study design

Study participants

Interventions

Sample size

Randomization and blinding

Primary outcome

Secondary outcomes

Statistical Analysis

Results

Demographics

Primary outcome: FSFI

Secondary outcome measures

SSEs

FSDS-R, PSS-10, and SF-12

Hormonal assessment

Hematological and biochemical parameters

Safety assessment

Discussion

Conclusion

Declarations

Author contributions

Funding

Conflicts of interest

Data availability

Acknowledgements

References

Additional Declarations

Supplementary Files

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