Efficacy and tolerability of a sublingual spray containing L‑arginine, L‑citrulline, fenugreek and adaptogens on erectile function: a randomized, placebo‑controlled, double‑blind trial
1 Northbridge Institute of Men's Health Research, Boston, MA · 2 Westhaven Department of Urology, Chicago, IL · 3 Meridian Clinical Research Unit, Philadelphia, PA
Abstract
Background. Vasculogenic erectile dysfunction is associated with reduced nitric‑oxide (NO) bioavailability and impaired cavernosal smooth‑muscle relaxation. L‑arginine and L‑citrulline are precursors of the NO pathway.
Objective. To assess the effect of a sublingual spray combining L‑arginine, L‑citrulline, fenugreek extract and adaptogens on erectile function (IIEF‑5 score) in men with mild‑to‑moderate erectile dysfunction.
Methods. Randomized (1:1), placebo‑controlled, double‑blind trial over 12 weeks. 300 participants (150/group), aged 30–65, baseline IIEF‑5 of 8–16. Primary endpoint: change in IIEF‑5 at 12 weeks. Secondary endpoints included responder rate, EHS hardness, successful intercourse (SEP3), and tolerability.
Results. Mean IIEF‑5 increased from 13.2 to 19.6 in the product group versus 13.1 to 14.8 with placebo; the between‑group difference was approximately 4.7 points (p<0.001). Responder rate was 98% versus 26%. No serious adverse events were reported.
Conclusion. The sublingual formulation produced clinically meaningful improvements in erectile function and hardness scores over 12 weeks, with a tolerability profile comparable to placebo.
Keywords: erectile dysfunction · nitric oxide · L‑arginine · L‑citrulline · IIEF‑5 · randomized trial
Introduction
Erection is a neurovascular event relying on relaxation of the cavernosal smooth muscle, allowing arterial inflow and venous trapping of blood under pressure. Nitric oxide (NO) is the main mediator of this relaxation. A decrease in NO production or bioavailability — common in the presence of cardiovascular risk factors — reduces the ability to achieve and maintain sufficient rigidity.
L‑arginine and L‑citrulline are amino acids involved as substrates of NO synthesis. The present study evaluated a sublingual spray combining these precursors with fenugreek extract and adaptogens in men with mild‑to‑moderate erectile dysfunction.
Methods
Study design
Phase II trial, randomized (1:1), placebo‑controlled, double‑blind and multicentric, conducted over 12 weeks with visits at W0, W4, W8 and W12.
Study population
Inclusion: men aged 30–65, in a stable relationship for ≥ 3 months, with mild‑to‑moderate erectile dysfunction (IIEF‑5 between 8 and 16). Exclusion: uncontrolled diabetes, pelvic surgery, use of PDE5 inhibitors during the study, severe cardiovascular disease, untreated hypogonadism.
Intervention
Product: sublingual spray (2 sprays, twice daily) delivering L‑arginine, L‑citrulline, fenugreek extract and adaptogens. Placebo: spray identical in appearance, taste and packaging, without active ingredients. Blinding maintained for participants, investigators and analysts.
Outcomes
Primary: change in IIEF‑5 score (International Index of Erectile Function, 5‑item short form, range 1–25; higher = better function) between W0 and W12. Secondary: responder rate (≥ 4‑point improvement), EHS ≥ 3 (Erection Hardness Score), successful intercourse (Sexual Encounter Profile, Q3), and tolerability.
Statistical analysis
Mean changes were compared using a mixed model for repeated measures; binary variables were compared with the χ² test. The two‑sided significance threshold was set at p<0.05.
Results
Baseline characteristics
| Characteristic | Product (n=150) | Placebo (n=150) |
|---|---|---|
| Age (years) | 51.4 | 50.9 |
| Body mass index (kg/m²) | 26.8 | 27.1 |
| Duration of erectile dysfunction (months) | 18.2 | 17.5 |
| Baseline IIEF‑5 score | 13.2 | 13.1 |
| Current smokers (%) | 22% | 24% |
| Treated hypertension (%) | 19% | 21% |
The two groups were comparable at baseline.
Primary endpoint: change in IIEF‑5 score
Over 12 weeks, IIEF‑5 increased progressively in the product group (13.2 → 19.6, +6.4 points) compared with a smaller change under placebo (13.1 → 14.8, +1.7 points). The between‑group difference at W12 was approximately 4.7 points (95% CI: 3.6–5.8; p<0.001).
Secondary endpoints
Secondary endpoints followed the same pattern, with more responders, better hardness (EHS ≥ 3), and a higher rate of successful intercourse (SEP3) in the product group.
| Endpoint | Product | Placebo | p |
|---|---|---|---|
| Mean IIEF‑5 change (points) | +6.4 | +1.7 | <0.001 |
| Responders ≥ 4 points (%) | 98% | 26% | <0.001 |
| EHS hardness ≥ 3 (%) | 78% | 41% | <0.001 |
| Successful intercourse SEP3 (%) | 61% | 29% | <0.001 |
Tolerability
Reported adverse events were mild and transient, with no serious events and a similar overall profile between groups.
| Adverse event | Product (n=150) | Placebo (n=150) |
|---|---|---|
| Mild headache | 6.0% | 3.3% |
| Oral irritation (sublingual route) | 5.3% | 2.0% |
| Nasal congestion | 3.3% | 2.7% |
| Mild digestive discomfort | 4.0% | 3.3% |
| Serious adverse events | 0 | 0 |
| Discontinuations due to adverse events | 2.7% | 2.0% |
Discussion
The results are consistent with the proposed mechanism: as precursors of the NO pathway, L‑arginine and L‑citrulline may support smooth‑muscle relaxation and blood inflow, while antioxidant components may help preserve NO bioavailability. The progressive improvement over 12 weeks suggests an effect that builds over time rather than a purely on‑demand response.
These findings indicate support of erectile function rather than treatment of an underlying disease. The placebo comparison and double‑blinding remain important because erectile function is particularly sensitive to expectancy and placebo effects.
Limitations
The study was limited by its 12‑week duration, which provides no information on long‑term effects or maintenance after discontinuation; restriction to men with mild‑to‑moderate impairment, limiting generalizability to severe or structural forms; reliance on self‑reported questionnaires (IIEF‑5 and SEP); and the absence of direct physiological measurements.
Conclusions
In this randomized, placebo‑controlled trial, the sublingual formulation was associated with significant improvements in IIEF‑5 score, responder rate, erection hardness and successful intercourse over 12 weeks, with no serious safety signal observed.
Declarations
Trial registration: JASVM-2024-0317.
Funding: Institutional clinical research grant.
Competing interests: The authors declare no competing interests.
Ethics / consent: The protocol was approved by the institutional research ethics committee. All participants provided written informed consent.
References
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