It’s a bit different as 20 mg tid of sildenafil will give little spikes then be metabolized rapidly. So if the beneficial effect proposed due to PDE5 agents is due to short duration more intense spikes in inhibition, then not equivalent - however if the benefit is due to ongoing constant PDE5 activity, then tadalafil 5 mg daily will have a larger effect and be continuously present due to it’s long half life. The modeling I see is that 5 mg/day is giving a steady state of ~8 mg of tadalafil average effect. The intensity is similar to 20 mg TID of sildenafil, but the pattern is different and the time of exposure will be much greater with tadalafil.
I think other benefits are a modest decrease in blood pressure and observational data indicating a modest decrease in cardiac events, heart failure and endothelial dysfunction.
The data in regard to dementia seems equivocal and I’m not convinced one way or the other, but for vascular disease, I’m favoring having these agents.
Specifically the risk of serous retinal detachment went up. This is a fairly rare cause of retinal detachment and is actually treated medically usually.
And certainly some of the risk factors for ED are also risk factors for retinal detachment so it is challenging to say based on observational studies that is is true.
I’m not convinced about the dementia data either but watching.
Was there a % occurrence indicated for retinal detachment?
After correcting for multiple comparisons, genetically proxied PDE5 inhibition, per one SD lower in diastolic blood pressure, was associated with higher odds of Alzheimer’s disease (OR 1.09, 95% CI 1.07–1.11) and Lewy body dementia (OR 1.32, 95% CI 1.23–1.41), but a trend towards lower odds of vascular dementia across all instruments.
The mean SD of 24-hour DBP was 13.0 +/- 2.6 mm Hg (12.1 +/- 2.8 at the day and 9.8 +/- 3.0 at night).
Isn’t that what should be observed? Whether or not PDE5s drop your DBP by 12 points?
Depends on the study. One was like .04% per year compared to .02% in non users.
5mg daily Tadalafil showed very little decrease in either blood pressure number
Remember PDE5’s performed extremely well in this uk Biobank data that was widely discussed from 2024 as far as lowering mortality risk is concerned
What would you suggest as a daily dose for Sildenafil? I was doing Tadalafil, but I can’t cope with the sides, and Sildenafil seems to have way fewer side effects for me but can’t figure what a proper/best daily dose would be.
Probably 25-50mg
I’m doing 25 but was thinking doing only 12.5 since it is every day and don’t have ED issues. Don’t know if anyone is doing that little? or if it is worth taking such low dose for off label use.
I think 12.5mg Sildenafil might be too low. I think 25mg is probably the lowest dose worth using. I think 50mg is probably the sweet spot for daily use but I’m just speculating. I’m personally only using 2.5mg Tadalafil hoping it’s enough but I know 5mg is better. But like you, I don’t like the side effects.
I won’t be throwing my Tadalafil away anytime soon
AI analysis from Vera: Systematic review and meta-analysis of cohort studies including 1,257,759 men with erectile dysfunction (with or without coronary artery disease). PDE5 inhibitor use was associated with a 22% reduction in major adverse cardiovascular events (RR 0.78, 95% C| 0.69-0.89) and a 30% reduction in all-cause mortality (RR 0.70, 95% C| 0.56-0.87) over a median follow-up of 4.3 years.
From 2025
https://www.amjmed.com/article/S0002-9343(24)00705-8/fulltext?utm_source=chatgpt.com
The final cohort included 509,788 men with erectile dysfunction and 1,075,908 with lower urinary tract symptoms. Tadalafil and sildenafil were associated with significantly reduced risks of all-cause mortality (RR 0.66/0.76), myocardial infarction (0.73/0.83), stroke (0.66/0.78), venous thromboembolism (0.79/0.80), and dementia (0.68/0.75) in erectile dysfunction patients, with tadalafil showing more significant benefits. In lower urinary tract symptom patients, tadalafil was similarly associated with reduced mortality, cardiovascular disease, and dementia.
The confounders are massive in those studies. What’s the comparison? Someone taking sildenafil or tadalafil has a partner (= emotional support), an active sex life (= happiness), and is proactive towards their health (= probably similarly proactive in other areas). Massive healthy user bias. That’s why those longitudinal studies should just be hypothesis-generating. Then if not confirmed by MR and clinical trials: most likely trash/confounding.
I agree, the only trouble is the current MR trials are trash too:
PDE5 inhibitors are weak systemic antihypertensives. So Brennan and Tinworth (2025) used systemic blood pressure as a mathematical proxy for a drug that doesn’t actually lower systemic blood pressure very much in real life, their study likely captured the neurological risks of lifelong lower blood pressure, rather than the real-world effects of taking a PDE5 inhibitor.
Re Lewy Body Dementia: clinical consensus points to an optimum blood pressure target that is notably higher and more flexible than standard guidelines—specifically aiming for a systolic target around 130 to 140 mmHg. Basically hyperperfusion due to low blood pressure is thought to be a risk factor for the brain stem, causing LBD.
Summary : ignore the current MR studies - they’re useless because they don’t identify pde5 inhibition genes.
I copied your message in ChatGPT 5.5 Thinking Extended and asked its opinion. Conclusion:
I would not ignore Brennan & Tinworth, but I would downgrade it heavily for real-world decision-making.
Best interpretation:
For occasional sildenafil/tadalafil use: this MR paper should probably change your risk estimate only slightly, if at all.
For chronic daily tadalafil as a “brain health” intervention: it is a real caution flag. The evidence is too conflicted to assume benefit, and the LBD signal in particular may partly reflect BP/autonomic/hypoperfusion biology rather than direct PDE5 inhibition.
For PDE5 inhibitors as dementia-prevention drugs: current evidence is not convincing. Clinical trials and better pharmacoepidemiology matter more than this MR signal alone.
I disagree with this completely. When certain patterns are strong and results speak for themselves then to me that is the best study one can have/hope for. Finding confounders is like making excuses to deny reality. There are no coincidences and/or confounders when results are overwhelming. A
s an example you say having a partner =emotional support, it is the opposite for a lot of people, you get better emotional support from an animal/pet. For me and I know for many of my friends’ long-term relationships tend to add a bit of stress and not the opposite. We are not made well to deal with the BS that woman go through and throw at us LOL, so IMO that confounder is null at best, or the opposite at worst.
I’d also read a study (as an example) that people in high altitudes had much lower incidences of CVD and then toward the end of the study the mentioned that it may be the case that people are more active, to me that is total BS to undermine something that is very real and obvious.
The data is pretty clear for men that marriage is a huge longevity intervention. Has been known for 50+ years.
So what you or your friends might interpret as stress maybe is good stress.
The data is pretty close to irrefutable despite lots of confounders. Certainly mental illness is bad for longevity and the more severe tend to be single.
There is a huge healthy user bias and probably a marriage bias in PDE5 studies. Doesn’t completely negate it in my opinion but I don’t deny the bias is there.
But that’s the whole point: the evidence in favor of sildenafil/tadalafil is NOT strong. Many papers found nothing and Mendelian randomization is negative. The few studies that found benefits often do not find a dose-response relationship and are poorly controlled for confounders.
Well, I thought our friend @LukeMV posted few studies showing pretty convincing benefits. So, I don’t know maybe now it’s become mine is better than yours (studies) lol. To be fair, I do get somewhat of a less clear vision when using either (Cialis a bit more so) and that definitely is a turn off, but the benefits are also HUGE (as in performing better than in your 20’s) if nothing else the EGO man, holly molly big boost LOL. Maybe I’ll use them more sparingly or as needed but there are definitely benefits to be had knowing that you’ll be more of a man than you’ve ever been. Nothing more depressing for a man than a limp limb😂