blister pack

PDE5 Inhibitors

  • Drugs
  • Updated August 11, 2016

Phosphodiesterase 5 (PDE5) is an enzyme that affects cell signaling. Inhibiting PDE5 can relax muscles and increase blood flow to specific areas of the body, which is why PDE5 inhibitors such as tadalafil (Cialis™), sildenafil (Viagra™), and vardenafil (Levitra™) are primarily used to treat erectile dysfunction in men. Preclinical studies have reported potential neuroprotective properties of PDE5 inhibitors, but no human research has confirmed these potential benefits. People who use nitrate drugs should not take PDE5 inhibitors due to safety concerns.


While some clinical trials have examined acute effects of PDE5 inhibitors on cognitive function, no studies have tested whether PDE5 inhibitors can prevent age-related cognitive decline or dementia. Our search identified:

• 3 randomized controlled trials examining acute effects of PDE5 inhibitors on cognitive functions
• 1 uncontrolled clinical trial examining the effects of udenafil (Zydena™) on cognitive functions
• Numerous preclinical studies

Potential Benefit

Three small randomized controlled trials examining acute effects of PDE5 inhibitors observed no changes in cognitive functions in healthy adults [1-3]. A fourth trial from South Korea did report improved cognitive function, but the results are not reliable because it did not apply a randomized design and lacked a control group [4].

In preclinical studies, PDE5 inhibitors protect against cognitive impairment and neurodegeneration [5-9]. Some proposed mechanisms include reduced tau tangles (a component of Alzheimer's disease), increased protective molecules such as brain-derived neurotrophic factor (BDNF), reduced inflammation, and reduced cell-death signaling, but none of these effects have been demonstrated in humans yet. Given the widespread use of PDE5 inhibitors, it is surprising that no human clinical studies have examined whether people taking PDE5 inhibitors have an altered risk of cognitive impairment or dementia.

For Dementia Patients

No clinical studies have been carried out to test whether PDE5 inhibitors can benefit someone with dementia. While some benefits such as decreased biological markers of Alzheimer's disease (e.g., tau phosphorylation) and improved cognitive functions have been observed in preclinical studies [5][6], these benefits have not been confirmed in people with dementia.


PDE5 inhibitors are well-tolerated in most people and side effects are generally mild and include headache, flushing, back pain, diarrhea, and gastric symptoms [10-12]. Rare side effects include vision changes or sudden vision loss, particularly in people with heart disease or diabetes. PDE5 inhibitors can also cause prolonged or painful erections, which can cause permanent damage unless treated.

PDE5 inhibitors can interact with some medications and should not be used if you are taking a nitrate drug for chest pain or heart problems, as this can lead to a sudden and serious decrease in blood pressure. Other potentially dangerous interactions are discussed at

NOTE: This is not a comprehensive safety evaluation or complete list of potentially harmful drug interactions. It is important to discuss safety issues with your physician before taking any new supplement or medication.

How to Use

In the US, tadalafil (Cialis™), sildenafil (Viagra™), vardenafil (Levitra™), and avanafil (Stendra™) are on the market to treat erectile dysfunction. Sildenafil (Revatio™) and tadalafil (Adcirca™) are also indicated for the treatment of pulmonary hypertension. None of these drugs are approved for treating cognitive decline or dementia. PDE5 inhibitors should not be used if you take nitrate medications, due to the risk of severe and possibly fatal drop in blood pressure.

Learn More

The Patient Education Center by Harvard Health Publications provides an online comparison of different PDE5 inhibitors.

ADDF is sponsoring a clinical trial led by Dr. Atticus Hainsworth at St. George's, University of London, which examines the effectiveness of tadalafil in treating people with vascular cognitive impairment (a potential precursor to vascular dementia). Details of this trial can be found by searching "Hainsworth" in the ADDF's Online Portfolio and at

Check for drug-drug and drug-supplement interactions on


  1. Reneerkens OA, Sambeth A, Ramaekers JG et al. (2013) The effects of the phosphodiesterase type 5 inhibitor vardenafil on cognitive performance in healthy adults: a behavioral-electroencephalography study. J Psychopharmacol 27, 600-608.
  2. Schultheiss D, Muller SV, Nager W et al. (2001) Central effects of sildenafil (Viagra) on auditory selective attention and verbal recognition memory in humans: a study with event-related brain potentials. World journal of urology 19, 46-50.
  3. Theunissen EL, Heckman P, de Sousa Fernandes Perna EB et al. (2015) Rivastigmine but not vardenafil reverses cannabis-induced impairment of verbal memory in healthy humans. Psychopharmacology (Berl) 232, 343-353.
  4. Shim YS, Pae CU, Kim SW et al. (2011) Effects of repeated dosing with Udenafil (Zydena) on cognition, somatization and erection in patients with erectile dysfunction: a pilot study. International journal of impotence research 23, 109-114.
  5. Cuadrado-Tejedor M, Hervias I, Ricobaraza A et al. (2011) Sildenafil restores cognitive function without affecting beta-amyloid burden in a mouse model of Alzheimer's disease. British journal of pharmacology 164, 2029-2041.
  6. Garcia-Barroso C, Ricobaraza A, Pascual-Lucas M et al. (2013) Tadalafil crosses the blood-brain barrier and reverses cognitive dysfunction in a mouse model of AD. Neuropharmacology 64, 114-123.
  7. Puzzo D, Loreto C, Giunta S et al. (2014) Effect of phosphodiesterase-5 inhibition on apoptosis and beta amyloid load in aged mice. Neurobiology of aging 35, 520-531.
  8. Rutten K, Basile JL, Prickaerts J et al. (2008) Selective PDE inhibitors rolipram and sildenafil improve object retrieval performance in adult cynomolgus macaques. Psychopharmacology (Berl) 196, 643-648.
  9. Zhang J, Guo J, Zhao X et al. (2013) Phosphodiesterase-5 inhibitor sildenafil prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in APP/PS1 transgenic mice. Behavioural brain research 250, 230-237.
  10. Gao L, Yang L, Qian S et al. (2016) Systematic review and meta-analysis of phosphodiesterase type 5 inhibitors for the treatment of female sexual dysfunction. Int J Gynaecol Obstet 133, 139-145.
  11. Giannetta E, Feola T, Gianfrilli D et al. (2014) Is chronic inhibition of phosphodiesterase type 5 cardioprotective and safe? A meta-analysis of randomized controlled trials. BMC Med 12, 185.
  12. He CJ, Chen SJ, Wang J et al. (2015) Efficacy and safety of phosphodiesterase type-5 inhibitors for pulmonary arterial hypertension: A meta-analysis focusing on 6MWD. Pulm Pharmacy There 32, 24-28.