EnoSTIM™ (Apple-Grape-Saffron for Male Sexual Health)

Evidence Level
Preliminary
2 Clinical Trials
5 Documented Benefits
1/5 Evidence Score

EnoSTIM™ is a proprietary blend developed by Nexira (France) for male sexual health, combining apple polyphenols, grape polyphenols and saffron extract, taken at 600 mg/day. The only study of the finished blend is a manufacturer-funded, open-label observational study in men aged 45 to 65: 103 men started and 94 completed, and over 28 days the average Erection Hardness Score rose from 2.7 to 3.3 while 74% of participants improved. Every participant received the product and there was no placebo group, so none of that change can be attributed to the supplement rather than to expectation or repeated questioning. The eNOS and antioxidant figures quoted in trade materials — blood flow 'up to 50%', oxidative stress 'down 74%' — come from unpublished laboratory and animal work, not from people. No randomised placebo-controlled trial of EnoSTIM™ has been published, and the human trial evidence on this page comes from saffron and from grape polyphenols tested separately, not from this blend.

Studied Dose 600 mg/day (the dose used in the manufacturer's uncontrolled 28-day observational study)
Active Compound Apple polyphenols + Grape polyphenols + Saffron extract (proprietary synergistic ratio)

Benefits

Male Sexual Performance / Hardness Score Improvement

In a manufacturer-funded, open-label observational study, men aged 45 to 65 with an Erection Hardness Score of 2 to 3 took EnoSTIM™ 600 mg/day for 28 days; 103 started and 94 completed. Mean Erection Hardness Score rose from 2.7 to 3.3, mean IIEF-5 rose from 15.6 to 17.7, and 74% of participants improved their hardness score. Because there was no placebo group, 74% is a responder rate rather than an effect size: placebo responder rates in erectile-function studies are typically substantial, and without a comparison arm the supplement's own contribution cannot be separated out. The report was not published in a PubMed-indexed journal.

Endothelial Nitric Oxide Synthase (eNOS) Activation

Laboratory work reported by the manufacturer (in vitro and ex vivo) describes activation of endothelial nitric oxide synthase, the enzyme that makes nitric oxide for vasodilation, together with an increase in flow of up to 50% in that laboratory model. No peer-reviewed publication of these experiments was located, and a flow figure obtained in cells and isolated tissue is not a measurement of blood flow in people. Blood flow has not been measured in any published human study of EnoSTIM™.

Antioxidant Activity (Animal and Laboratory Only)

An unpublished animal study reported by the manufacturer describes free-radical scavenging and a 74% fall in an oxidative stress measure. No peer-reviewed publication of this work was located, and no oxidative stress marker has been measured in people taking EnoSTIM™, so the figure should not be read as a human result. Oxidative stress in blood vessels is one of several factors discussed in age-related decline in erectile function.

Healthy Blood Flow Properties

The proposed vascular rationale combines the laboratory eNOS finding with the animal antioxidant finding. Blood flow, flow-mediated dilation and blood pressure have not been measured in any published human study of EnoSTIM™, so this remains a mechanism hypothesis rather than a demonstrated effect on vascular or cardiovascular health.

Saffron Synergy for Sexual Health

Saffron on its own has been tested for sexual function with mixed results. A 4-week trial in 36 men whose sexual difficulty was caused by fluoxetine found improvement in erectile function at 30 mg/day, while the largest trial — 346 men with erectile dysfunction given 30 mg twice daily for 12 weeks — found no benefit on any measure. The manufacturer describes the saffron in a 600 mg serving in relation to a 28 mg/day intake, which is close to the amount used in the small positive trial and about half the amount used in the large null trial. There is no EFSA-authorised health claim for saffron and erection: claims of that kind are unassessed 'on-hold' applications submitted by member states, which EFSA has not evaluated since the European Commission suspended botanical claim assessment in 2010, and which EU courts have held may not be used to advertise a product. Whether the three components act together has not been tested.

Mechanism of action

1

eNOS Activation → Increased Nitric Oxide → Vasodilation

The proposed mechanism is activation of endothelial nitric oxide synthase, raising nitric oxide production in the vascular endothelium and promoting vasodilation and blood flow. Nitric oxide signalling is central to normal erection, since filling of the corpora cavernosa depends on adequate blood flow. This sequence has been described only in laboratory experiments supplied by the manufacturer and has not been demonstrated in people taking EnoSTIM™. EnoSTIM™ is a food supplement, not a medicine, and has not been compared with, and should not be assumed to work like, prescription erectile dysfunction drugs.

2

Antioxidant Protection of NO

Nitric oxide is rapidly inactivated by reactive oxygen species. The proposal is that polyphenol antioxidant activity slows that inactivation and preserves nitric oxide availability. Nitric oxide bioavailability has not been measured in people taking EnoSTIM™, so this step is inferred from laboratory work rather than shown. Oxidative stress is one of several factors discussed in age-related changes in sexual function.

3

Apple + Grape Polyphenols

Combined polyphenol fraction provides antioxidant activity, vascular endothelial support, anti-inflammatory effects. Complementary mechanisms to saffron's serotonergic and circulatory effects.

4

Saffron Sexual Health Mechanism

Saffron has been studied for effects on sexual function through several proposed pathways, including neurotransmitter modulation and mood effects, and trial results are mixed rather than consistent. Saffron holds no EFSA-authorised health claim for erection or for muscle relaxation. Entries described as 'pending' are on-hold applications that EFSA has never assessed, because the European Commission suspended evaluation of botanical health claims in 2010, leaving more than 2,000 such applications unexamined; an unexamined application is not evidence and not an approval.

Clinical trials

1
EnoSTIM™ in Men Aged 45-65 — Open-Label Observational Study, No Control Group

Allaert F, Guillemet D, Schueller R, Herpin F (2021). Open-label observational study of EnoSTIM™ 600 mg/day for 28 days; 103 enrolled, 94 analysed. Funded by Nexira; one author is Nexira's director of scientific development and the other three are affiliated with the evaluation centre that ran the study. Published in Archives in Biomedical Engineering & Biotechnology, a journal not indexed in PubMed.

94 men aged 45 to 65 reporting an Erection Hardness Score of 2 to 3. No placebo or comparison group — every participant received the product.

Mean Erection Hardness Score rose from 2.7 to 3.3 over 28 days and mean IIEF-5 from 15.6 to 17.7; 74% of participants improved their hardness score, and the reported proportion of erections firm enough for penetration rose from 68.0% to 87.7%. All of these are within-group changes in an uncontrolled study, so none of them can be attributed to the supplement rather than to placebo response, expectation or repeated questioning.

2
EnoSTIM™ eNOS Activation — Laboratory Experiments (Not a Human Trial)

In vitro and ex vivo experiments on eNOS activity and vessel flow, reported by the manufacturer. No peer-reviewed publication of this work was located in PubMed.

Cells and isolated tissue. No human participants.

Reported activation of eNOS and an increase in flow of up to 50% in the laboratory model. Laboratory results of this kind do not establish any effect on blood flow or on erectile function in people.

Side effects and drug interactions

Common Potential side effects

Generally well tolerated in the single 28-day observational study, in which 103 men took the product and 94 completed; there are no longer-term and no placebo-controlled safety data on this blend.
Mild GI distress (rare).
Headache rare.
Dizziness from vasodilation (rare).
Allergic reactions to ingredients rare.
Saffron-related cautions (Asteraceae family allergy).

Important Drug interactions

PDE5 inhibitors (sildenafil, tadalafil, vardenafil) — additive vasodilation; theoretical hypotension; consult prescriber.
Nitrates (nitroglycerin, isosorbide) — additive NO/vasodilation; theoretical severe hypotension; avoid combination.
Antihypertensives — additive BP reduction; modest concern.
Anticoagulants — theoretical antiplatelet effects from polyphenols; minor.
Antidepressants — saffron component has serotonergic activity; theoretical interaction.
Pregnancy — N/A (male product); consult for partner safety if relevant.

Frequently asked questions about EnoSTIM™ (Apple-Grape-Saffron for Male Sexual Health)

What is EnoSTIM?

EnoSTIM™ is a proprietary blend developed by Nexira (France) for male sexual health, combining apple polyphenols, grape polyphenols and saffron extract, taken at 600 mg/day.

What is EnoSTIM used for?

EnoSTIM is researched primarily for Men's Health. In a manufacturer-funded, open-label observational study, men aged 45 to 65 with an Erection Hardness Score of 2 to 3 took EnoSTIM™ 600 mg/day for 28 days; 103 started and 94 completed. Mean Erection Hardness Score rose from 2.7 to 3.

What is the recommended dosage of EnoSTIM?

The clinically studied dose is 600 mg/day (the dose used in the manufacturer's uncontrolled 28-day observational study) Always follow the product label and check with a healthcare provider for personal advice.

Is EnoSTIM safe, and does it have side effects?

For most healthy adults, EnoSTIM is well tolerated at studied doses. Reported effects can include: Generally well tolerated in the single 28-day observational study, in which 103 men took the product and 94 completed; there are no longer-term and no placebo-controlled safety data on this blend. Mild GI distress (rare). It may also interact with some medications. EnoSTIM is not right for everyone, so check with a healthcare provider first if you are pregnant or breastfeeding, have a medical condition, or take prescription medication.

Does EnoSTIM interact with any medications?

Possible interactions include: PDE5 inhibitors (sildenafil, tadalafil, vardenafil) — additive vasodilation; theoretical hypotension; consult prescriber. Nitrates (nitroglycerin, isosorbide) — additive NO/vasodilation; theoretical severe hypotension; avoid combination. If you take prescription medication, check with a pharmacist or doctor before using it.

How strong is the scientific evidence for EnoSTIM?

NutraSmarts rates the evidence for EnoSTIM as Preliminary (1 out of 5). It is backed by 2 clinical trials and 6 cited references summarized on this page. A higher rating reflects more, larger, and better-designed human studies.

References(6 citations)

Evidence ratings on NutraSmarts are based on the totality of human clinical research, with emphasis on randomized controlled trials, meta-analyses, and systematic reviews. The references below directly support claims made throughout this page.

  1. Modabbernia A, Sohrabi H, Nasehi AA, Raisi F, Saroukhani S, Jamshidi A, Tabrizi M, Ashrafi M, Akhondzadeh S Effect of saffron on fluoxetine-induced sexual impairment in men: randomized double-blind placebo-controlled trial. Psychopharmacology. 2012;223(4):381-388. doi: 10.1007/s00213-012-2729-6.PubMedUsed to support: Randomised double-blind placebo-controlled trial in 36 married men with major depressive disorder stabilised on fluoxetine who reported sexual impairment; 30 completed. Saffron 15 mg twice daily (30 mg/day) for 4 weeks improved the International Index of Erectile Function erectile function domain (p<0.001), intercourse satisfaction (p=0.001) and total score (p<0.001) more than placebo, and 60% of the saffron group versus 7% of placebo reached a normal erectile function score. Saffron did not differ from placebo for sexual desire (p=0.517), orgasmic function (p=0.095) or overall satisfaction (p=0.334). The men were experiencing antidepressant-induced sexual difficulty rather than typical age-related change, the trial is small, and saffron was given alone rather than as part of this blend.
  2. Ranjbar H, Ashrafizaveh A Effects of saffron (Crocus sativus) on sexual dysfunction among men and women: A systematic review and meta-analysis. Avicenna Journal of Phytomedicine. 2019;9(5):419-427..PubMedUsed to support: Systematic review and meta-analysis pooling 5 trials with 173 participants, men and women combined, reporting a significant improvement in sexual dysfunction scores with saffron (standardised mean difference 0.811, 95% CI 0.356 to 1.265) and in pooled subscales (0.493, 95% CI 0.261 to 0.724), with substantial heterogeneity between studies (I-squared 60%). The evidence base is small, men and women are pooled together, and the review does not include the largest trial of saffron in erectile dysfunction, which found no benefit. Saffron was given alone, not as part of this blend.
  3. Odai T, Terauchi M, Kato K, Hirose A, Miyasaka N Effects of Grape Seed Proanthocyanidin Extract on Vascular Endothelial Function in Participants with Prehypertension: A Randomized, Double-Blind, Placebo-Controlled Study. Nutrients. 2019;11(12). doi: 10.3390/nu11122844.PubMedUsed to support: Randomised double-blind placebo-controlled study in 30 middle-aged Japanese adults with prehypertension (6 men and 24 women, aged 40 to 64) given grape seed proanthocyanidin extract 200 or 400 mg/day or placebo for 12 weeks. Flow-mediated dilation did not change. Mean systolic blood pressure in the 400 mg group fell by 13 mmHg over the 12 weeks, and in an ad hoc analysis restricted to the 21 non-smokers, arterial stiffness and pulse wave velocity improved more than placebo. The extract was grape seed given alone, most participants were women, and no measure of erectile or sexual function was taken.
  4. Safarinejad MR, Shafiei N, Safarinejad S An open label, randomized, fixed-dose, crossover study comparing efficacy and safety of sildenafil citrate and saffron (Crocus sativus Linn.) for treating erectile dysfunction in men naïve to treatment. International Journal of Impotence Research. 2010;22(4):240-250. doi: 10.1038/ijir.2010.10.PubMedUsed to support: The largest trial of saffron in erectile dysfunction: 346 treatment-naive men randomised to on-demand sildenafil for 12 weeks then saffron 30 mg twice daily for 12 weeks, or the reverse order. Saffron produced no significant improvement in any International Index of Erectile Function domain, in Sexual Encounter Profile diary questions, or in treatment satisfaction scores; 91.2% of men answered yes to the global efficacy question while on sildenafil versus 4.2% while on saffron. The authors concluded the findings do not support a beneficial effect of saffron in men with erectile dysfunction. Saffron was given alone and at roughly double the amount present in a 600 mg serving of this blend.
  5. Deley G, Guillemet D, Allaert FA, Babault N An Acute Dose of Specific Grape and Apple Polyphenols Improves Endurance Performance: A Randomized, Crossover, Double-Blind versus Placebo Controlled Study. Nutrients. 2017;9(8):917. doi: 10.3390/nu9080917.PubMedUsed to support: Randomised double-blind crossover trial in 48 physically active men (mean age 31) given 500 mg of a grape and apple polyphenol preparation from the same manufacturer, or placebo, the evening before testing and again one hour before. Time to exhaustion in a high-intensity endurance test increased by 9.7% versus placebo, and maximal perceived exertion was reached later. This is the published human evidence for the apple-and-grape polyphenol part of the blend, and the outcome measured was exercise endurance, not blood flow, erectile function or any sexual health measure. The study was funded by the ingredient manufacturer and one author is a manufacturer employee.
  6. Borrelli F, Colalto C, Delfino DV, Iriti M, Izzo AA Herbal Dietary Supplements for Erectile Dysfunction: A Systematic Review and Meta-Analysis. Drugs. 2018;78(6):643-673. doi: 10.1007/s40265-018-0897-3.PubMedUsed to support: Systematic review and meta-analysis of 24 randomised controlled trials covering 2,080 men with erectile dysfunction. Ginseng significantly improved erectile function (standardised mean difference 0.43, 95% CI 0.15 to 0.70), while the three saffron trials (397 men) produced mixed results and were grouped by the authors with Tribulus terrestris rather than among the agents with consistent benefit. Study quality varied, with only 7 of the 24 trials judged to have a prevalent low risk of bias, and the review concluded that more research is needed before herbal products can be recommended for erectile dysfunction.