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PDE5 Inhibitors

  • Drugs
  • Updated March 25, 2022

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. In observational studies, sildenafil is associated with reduced risk for cardiovascular disease and dementia. Small clinical trials suggest PDE5 inhibitors may modestly improve blood flow to the brain, but there is no clear evidence that they improve cognitive function. People who use nitrate drugs should not take PDE5 inhibitors due to safety concerns.

Evidence

Small clinical trials have examined acute effects of PDE5 inhibitors on cognitive function and/or cerebral blood flow. An observational study examined the relationship between sildenafil use and dementia risk. Our search identified:

  • 1 systematic review for studies assessing PDE5 inhibitors for cerebral blood flow
  • 3 randomized controlled trials examining acute effects of PDE5 inhibitors on cognitive functions in healthy adults
  • 1 placebo-controlled trial examining the effects of tadalafil on cerebral blood flow in adults with small vessel disease
  • 2 uncontrolled clinical trials examining the acute effects of sildenafil on cerebral blood flow in Alzheimer’s disease
  • 1 uncontrolled trial examining the effects of tadalafil on cerebral blood flow and cognition in men with erectile dysfunction and mild cognitive impairment
  • 1 uncontrolled clinical trial examining the effects of udenafil (Zydena™) on cognitive functions in men with erectile dysfunction
  • 1 uncontrolled clinical trial examining the effects of tadalafil on cognitive function in men with benign prostatic hyperplasia
  • 1 observational study examining the relationship between sildenafil use and dementia risk
  • Numerous preclinical studies

Potential Benefit

An analysis of insurance claims in the United States found that individuals who had used sildenafil, based on their prescription history, had a lower incidence rate of Alzheimer’s disease, relative to individuals with the same chronic conditions that were not prescribed sildenafil [1]. Because sildenafil is primarily prescribed for erectile dysfunction, the majority of individuals in this analysis were men. Women prescribed sildenafil for pulmonary hypertension, high blood pressure in lung blood vessels, also showed a modestly lower risk for Alzheimer’s disease. Cardiovascular dysfunction can reduce blood flow to the brain, and is a risk factor for dementia. Since the conditions for which sildenafil is prescribed are associated with cardiovascular dysfunction, and the sildenafil use has also been associated with reducing adverse cardiovascular events in this population [2], the impact on dementia risk may be due to its effects on the cardiovascular system.

The brain requires increased blood flow to meet its energy demands while engaging in cognitively stimulating activity. By boosting the capacity for activity-dependent blood flow to the brain, PDE5 inhibitors could potentially improve performance on cognitively demanding tasks [3]. Thus far, minor benefits have only been seen in individuals with low baseline performance, and PDE5 inhibitors do not appear to act as cognitive enhancers in cognitively healthy adults.

While improvements to cognitive function relative to baseline were seen with PDE5 inhibitor use in men in two trials that lacked a control group, no changes in cognitive functions were observed in three small randomized controlled trials examining acute effects of PDE5 inhibitors in healthy adults [4; 5; 6; 7; 8].

For Dementia Patients

The ability of brain blood flow to increase in response to heightened cognitive activity is impaired in dementia patients. Small studies have found that PDE5 inhibitors can modestly increase cerebral blood flow at rest in patients with cognitive impairment, but did not adequately address whether treatment can restore the brain activity-dependent blood flow and cognitive function [9; 10; 11; 12].

Safety

PDE5 inhibitors are well-tolerated in most people and side effects are generally mild, including headache, flushing, back pain, diarrhea, and gastric symptoms [13; 14; 15]. 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 Drugs.com. 

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, while sildenafil (Revatio™) and tadalafil (Adcirca™) are 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 here.

Check for drug-drug and drug-supplement interactions on Drugs.com.

References

  1. Fang J, Zhang P, Zhou Y et al. (2021) Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer’s disease. Nature Aging 1, 1175-1188.
  2. Vestergaard N, Søgaard P, Torp-Pedersen C et al. (2017) Relationship between treatment of erectile dysfunction and future risk of cardiovascular disease: A nationwide cohort study. European Journal of Preventive Cardiology 24, 1498-1505.
  3. Pauls MM, Moynihan B, Barrick TR et al. (2018) The effect of phosphodiesterase-5 inhibitors on cerebral blood flow in humans: A systematic review. Journal of Cerebral Blood Flow & Metabolism 38, 189-203.
  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. Urios A, Ordoño F, García-García R et al. (2019) Tadalafil Treatment Improves Inflammation, Cognitive Function, And Mismatch Negativity Of Patients With Low Urinary Tract Symptoms And Erectile Dysfunction. Scientific Reports 9, 17119.
  6. 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.
  7. 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.
  8. 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 232, 343-353.
  9. Pauls MMH, Binnie LR, Benjamin P et al. (2022) The PASTIS trial: Testing tadalafil for possible use in vascular cognitive impairment. Alzheimer's & Dementia n/a.
  10. Sheng M, Lu H, Liu P et al. (2017) Sildenafil Improves Vascular and Metabolic Function in Patients with Alzheimer’s Disease. Journal of Alzheimer's Disease 60, 1351-1364.
  11. Samudra N, Motes M, Lu H et al. (2019) A Pilot Study of Changes in Medial Temporal Lobe Fractional Amplitude of Low Frequency Fluctuations after Sildenafil Administration in Patients with Alzheimer’s Disease. Journal of Alzheimer's Disease 70, 163-170.
  12. Choi JB, Cho KJ, Kim JC et al. (2019) The Effect of Daily Low Dose Tadalafil on Cerebral Perfusion and Cognition in Patients with Erectile Dysfunction and Mild Cognitive Impairment. Clin Psychopharmacol Neurosci 17, 432-437.
  13. 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.
  14. 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.
  15. 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 Pharmacol Ther 32, 24-28.