Viagra and Cognitive Function: What the Evidence Actually Shows

What is the human evidence, exactly?

The main human finding is one large analysis of insurance claims; the rest is laboratory work in cells and animals. The claims finding is an association, not proof that sildenafil improves cognition [1].

Viagra's approved indication is erectile dysfunction [2][4]. Revatio is approved for pulmonary arterial hypertension at different strengths and dosing [3].

What the 2021 claims analysis found

Fang and colleagues, publishing in Nature Aging, built a drug-repurposing screen and then tested the hit against insurance claims. Their retrospective case-control pharmacoepidemiologic analysis covered 7.23 million individuals. Sildenafil usage was associated with a 69% reduced risk of Alzheimer's disease: hazard ratio 0.31, 95% CI 0.25 to 0.39, P < 1.0×10-8 [1].

Propensity score stratified analyses confirmed the association across all four comparison drug cohorts tested (diltiazem, glimepiride, losartan and metformin) after adjusting for age, sex, race and disease comorbidities [1].

The same paper reported laboratory work: in neurons derived from induced pluripotent stem cells from Alzheimer's patients, sildenafil increased neurite growth and decreased phospho-tau expression [1]. That is a cell-culture result, not evidence about a person's memory.

What animal studies show

In rats given an embolic stroke, oral sildenafil at 2 or 5 mg/kg per day for 7 days, started 2 or 24 hours after stroke onset, significantly improved recovery on the foot-fault and adhesive-removal tests [5]. Infarct volume did not differ between treated and control animals. Treated rats had more bromodeoxyuridine-labelled cells in the subventricular zone and dentate gyrus and more immature neurons [5].

Cortical cGMP levels rose after sildenafil administration in those rats, and PDE5 mRNA was present in both ischemic and nonischemic brain tissue [5]. Rat stroke outcomes do not transfer automatically to people.

How the mechanism is described

During sexual stimulation, nitric oxide raises cGMP in the corpus cavernosum, relaxing smooth muscle and allowing blood in; sildenafil inhibits PDE5, the enzyme that breaks cGMP down, so it enhances that response [4].

Safety facts from the Viagra label

Nitrates. The Viagra label lists nitric oxide donors such as organic nitrates or organic nitrites in any form, taken regularly or intermittently, as contraindicated, and states that after a dose of Viagra it is unknown when nitrates can safely be given [4].

Blood pressure. A single 100 mg dose lowered supine blood pressure in healthy volunteers by a mean maximum of about 8.4/5.5 mm Hg [4]. When Viagra 100 mg was given with amlodipine 5 or 10 mg to hypertensive patients, supine pressure fell an additional 8/7 mm Hg [4].

Age. In healthy volunteers 65 and older, sildenafil AUC was about 84% higher and the active metabolite AUC about 107% higher than in younger men; unbound fractions were 45% and 57% higher [4]. The label suggests considering a 25 mg starting dose in this group [4].

Cardiac history. The label says there are no controlled clinical data on safety or efficacy in patients who have had a myocardial infarction, stroke or life-threatening arrhythmia within the previous 6 months, or who have resting blood pressure below 90/50 or above 170/110, cardiac failure or unstable angina; if prescribed, it says this should be done with caution [4].

Vision. Abnormal vision, mostly a colour tinge, light sensitivity or blurring, was reported by 1%, 2% and 11% of men on 25, 50 and 100 mg respectively, versus 1% on placebo [4]. Sudden vision loss can be non-arteritic anterior ischemic optic neuropathy; observational case-crossover studies suggest roughly a 2-fold increase in risk (estimates 2.15, 95% CI 1.06 to 4.34, and 2.27, 95% CI 0.99 to 5.20), and the label states these data do not substantiate a causal relationship [4]. The label says to stop Viagra and seek medical care for sudden vision loss or sudden hearing loss [4].

Combination. The Viagra label says combining it with Revatio or another PDE5 inhibitor has not been studied and may further lower blood pressure [4].

For product information, see sildenafil.

Bottom line

For erectile dysfunction, sildenafil's dosing and risks are set out on the label [4]. For cognition, the human finding discussed here is one large claims association between sildenafil use and a lower rate of Alzheimer's disease diagnoses, which its authors say cannot establish causality [1].