Sildenafil
Viagra
Sildenafil (Viagra) is a hormonal & sexual research compound. PDE5 inhibitor, same target as tadalafil but far shorter acting and more selective for PDE5 over PDE11 — which is why it causes less back and muscle ache and more visual disturbance (PDE6 crossover).
Sildenafil quick facts
| Reported research dose | 25–100mg as needed |
| Route | Oral |
| Frequency | 1x when used · As needed |
| Half-life | ~4 hours |
| Forms | Oral |
| Evidence level | The original PDE5 randomized-trial dataset |
Shorter and sharper than tadalafil, and genuinely blunted by a heavy meal in a way tadalafil isn't. Blue-tinged vision is a benign PDE6 effect. ⚠️ Never with nitrates.
How Sildenafil works
PDE5 inhibitor, same target as tadalafil but far shorter acting and more selective for PDE5 over PDE11 — which is why it causes less back and muscle ache and more visual disturbance (PDE6 crossover).
Proposed benefits
Researched for libido, hormonal signaling and reproductive / sexual function.
Where to get Sildenafil
Buy Sildenafil at AlgoRx →The evidence for Sildenafil
Graded by what exists behind each claim.
✅ Clinically validated
- Approved with extensive randomized data for erectile dysfunction and, at different dosing, for pulmonary arterial hypertension. Efficacy in ED is around 70% across trials.
📊 Correlative data
- Vast real-world use over 25 years. The safety profile is exceptionally well characterized, and the one absolute rule is unchanged: never with nitrates, where the combination can cause fatal hypotension.
🧪 Theoretical / extrapolated
- A PDE5 inhibitor — it prevents breakdown of cGMP, amplifying the nitric-oxide signal that relaxes vascular smooth muscle.
- It amplifies an existing signal rather than creating one, which is why arousal is still required and why it does nothing for desire. Cross-reactivity with PDE6 in the retina explains the blue-tinted vision some users report.
How to read these tiers: they say how much human evidence exists, not how well something works — and ✗ flags harm, never a disappointing trial. How the evidence tiers work →
What Sildenafil actually does
Sildenafil does not make nitric oxide, does not make cGMP and does not cause an erection. It stops one enzyme from clearing a second messenger. Nitrergic nerves and endothelium in the corpus cavernosum release nitric oxide, which activates soluble guanylate cyclase, which makes cGMP, which drops intracellular calcium and relaxes trabecular smooth muscle. Phosphodiesterase type 5 degrades that cGMP. Block PDE5 and the cGMP produced by an existing signal persists longer and reaches a higher concentration. That is the entire pharmacology, and it is why arousal is still required: with no NO signal there is no cGMP to protect.
The potency and the selectivity are both published numbers. Wallis 1999 reports an IC50 of 3.5 nM against PDE5, with 80- to 19,000-fold selectivity over PDE1 to PDE4; the original characterization Boolell 1996 gives a mean IC50 of 0.0039 µM, which is 3.9 nM — the same number to within the difference between two enzyme preparations. The label states the family profile: greater than 4,000-fold selective for PDE5 over PDE3, the cardiac contractility enzyme, and more than 700-fold over PDE2, PDE4, PDE7 through PDE11 US Food and Drug Administration 2014.
And then there is the one number that is small, which is the whole visual story. Selectivity over PDE6 — the phosphodiesterase of retinal rods and cones, which is structurally the closest relative of PDE5 — is only 10-fold US Food and Drug Administration 2014 Wallis 1999. Ten-fold is nothing. At 100 mg a meaningful fraction of retinal PDE6 is inhibited, phototransduction shutoff slows, and the result is the blue-green tinge and light sensitivity the label records as abnormal vision in 11% of men at that dose against 1% on placebo. It is a mechanism-obligatory effect, not an idiosyncrasy. Wallis 1999 adds the reassuring half: the plasma concentrations that produce retinal effects were about 30-fold higher than those active on intracavernosal pressure.
Where the class differences come from. Tadalafil's long duration and its back and muscle ache come from a different selectivity profile against PDE11; sildenafil's is more than 700-fold selective over PDE11 US Food and Drug Administration 2014 and it is the PDE6 window that is narrow instead. So the two drugs trade one off-target for another — sildenafil buys color vision changes and avoids myalgia, tadalafil the reverse. That is a real, mechanistic distinction and it is the correct basis for choosing between them.
One more consequence of PDE5's tissue distribution: it is also in systemic and pulmonary vascular smooth muscle. That is why the same molecule is licensed at a different dose for pulmonary arterial hypertension, why the label records flushing in 18% and headache in 28% at 100 mg, and why the nitrate interaction below is not a caution but a hard contraindication.
Cell, rodent, human — and where it stops
Step one, the enzyme and the isolated tissue. Boolell 1996 established inhibition of the cGMP-specific PDE at a mean IC50 of 0.0039 µM and showed relaxation in isolated human corpus cavernosum; Wallis 1999 carried the same pharmacology into anesthetized dogs, where the intravenous ED50 was 12–16 µg/kg against intracavernosal pressure.
Step two, the first human demonstration — and it was twelve men. Boolell 1996 reports a study in 12 patients with erectile dysfunction of no established organic cause, in whom sildenafil enhanced the duration and rigidity of erection in response to visual sexual stimulation, with no significant effect on heart rate or blood pressure. Twelve men is the entire proof-of-concept for one of the most-prescribed drugs of the last thirty years.
Step three, the registration trials, which met their endpoints. Goldstein 1998 reported two studies. A 24-week dose-response study in 532 men at 25, 50 and 100 mg, in which the mean score for achieving erections rose from 2.0 to 4.0 on a 0–5 scale at 100 mg — a 100% increase. And a 12-week flexible dose-escalation study in 329 men, in which 69% of intercourse attempts in the last four weeks succeeded on sildenafil against 22% on placebo, with a mean of 5.9 versus 1.5 successful attempts per month (p < 0.001). Of the 225 men entering the 32-week extension, 92% completed. Headache, flushing and dyspepsia occurred in 6–18%.
Step four, the timing study nobody quotes and everybody needs. Eardley 2002 measured onset in 17 men at 50 mg and duration in 16 at 100 mg, using penile rigidity monitoring rather than a diary. Median time to onset was 27 minutes, range 12–70 minutes; 71% were there by 30 minutes and 82% by 45. At 4 hours after a 100 mg dose the median duration of grade 3–4 erection was still 5 minutes against 0 on placebo — small, but not zero. So the honest window is roughly half an hour to four hours, with wide individual spread at the front end.
The obstacle, and it is about who was studied. Every efficacy number above came from men with diagnosed erectile dysfunction. There is no randomized evidence that a PDE5 inhibitor improves anything in a man with normal erectile function, which is a large share of actual use, and the mechanism predicts a ceiling there: you cannot amplify a signal that is already producing a full response. The second obstacle is that the trials measured a diary and a questionnaire, not the mechanism. No registration trial measured cavernosal cGMP, so the dose-response people experience is a clinical curve with a mechanistic explanation attached rather than a measured pharmacodynamic one.
Sildenafil pharmacokinetics — how much of it actually gets in
Route: oral, fast, and short. Absolute oral bioavailability is 41% (90% CI 36–47%) Nichols 2002, matching the label's 41% with a range of 25–63% US Food and Drug Administration 2014. Median time to peak in the fasted state is 60 minutes (range 30–120 minutes) and the terminal half-life is about 4 hours, with a volume of distribution of 105 L US Food and Drug Administration 2014.
The fatty-meal effect is real and it has been quantified twice. Nichols 2002 measured a mean delay in tmax of about one hour, a 29% reduction in Cmax (90% CI 19–38%) and an 11% reduction in AUC; the label reports the same 29% Cmax fall and 60-minute tmax delay US Food and Drug Administration 2014. Note what that means: the total exposure is barely touched, but the peak is cut by nearly a third and arrives an hour late. For a drug used in a two-hour window, peak and timing are the parameters that matter, which is why the practical advice about a heavy meal is correct even though the AUC change is trivial.
Dose proportionality is slightly worse than linear. Across 25–200 mg, doubling the dose predicts a 2.2-fold rise in Cmax and 2.1-fold in AUC Nichols 2002. Small, but it means the step from 50 mg to 100 mg buys a little more than double the exposure, and the side effects scale with it.
What degrades it, and the interaction arithmetic. Clearance is hepatic, principally by CYP3A4 with a minor CYP2C9 route US Food and Drug Administration 2014; Hyland 2001 identified the cytochromes responsible for N-demethylation to the active metabolite, which itself contributes to effect. The numbers on the label are large: ritonavir produces an 11-fold increase in AUC, cimetidine a 56% increase, and stronger azoles are expected to exceed ketoconazole's effect US Food and Drug Administration 2014. Age and organ function matter for the same reason — men over 65 run 84% to 107% higher AUC, and the label's answer in severe renal impairment, any hepatic impairment, or age over 65 is the same: consider starting at 25 mg. There is no injectable form; the intracavernosal comparator for erectile dysfunction is alprostadil, an entirely different molecule delivered by injection, and nothing about sildenafil's absorption is bypassable that way.
What would have to be true, and how you would know it was not
Three predictions with a measurable read-out. The third argues against a common expectation of the drug.
1. The erectile-function domain of the IIEF should move and the desire domain should not. The IIEF is the instrument the registration trials used, it is free, and it separates erectile function, orgasmic function, sexual desire, intercourse satisfaction and overall satisfaction into distinct scores. The mechanism amplifies an existing NO signal and touches nothing central, so over four weeks the erectile-function domain should rise clearly while the desire domain stays flat. If desire rises too, that is expectation, confidence or relief — all real effects, none of them PDE5 inhibition.
2. Onset should be measurably later after a heavy meal, and the size of the shift is predictable. Take 50 mg fasted and 50 mg 30 minutes after a high-fat meal on separate occasions and record time to usable response. Prediction from Nichols 2002: about an hour later and less firm at peak, with total duration roughly unchanged. This is the cheapest personal pharmacokinetic experiment on the site and it converts an argument into a number.
3. The prediction that cuts against it: this is not an endothelial treatment, and flow-mediated dilation should not stay improved once the drug is gone. PDE5 inhibition raises cGMP only while the drug is present, and the terminal half-life is about 4 hours US Food and Drug Administration 2014. So an FMD measurement 24 hours after a dose should be back at baseline. Anyone claiming a lasting vascular benefit from intermittent use is claiming something the half-life does not support, and FMD at 24 hours is the measurement that would falsify it. Pair it with hs-CRP at baseline and 12 weeks if the claim being tested is an anti-inflammatory one: the mechanism predicts no change.
What nobody has tested yet
Nobody has run the 30-fold retinal margin against the people who actually exceed it. Wallis 1999 reports that retinal effects required plasma concentrations roughly 30-fold above those active on intracavernosal pressure — a comfortable margin at 50 mg in a 40-year-old with normal liver function. It is not comfortable at 100 mg in a 70-year-old with 84–107% higher AUC US Food and Drug Administration 2014 who is also taking a CYP3A4 inhibitor. Contrast sensitivity and color discrimination testing in exactly that population, at peak, has not been published, and it is the group in whom the PDE6 window is narrowest.
Nobody has tested whether daily low-dose sildenafil does what daily low-dose tadalafil does. Daily dosing is an established pattern for the long-half-life drug and is essentially untested for the 4-hour one, because the pharmacokinetics look unsuited to it. But the question is whether a repeated daily cGMP pulse produces any cumulative endothelial change, and it has never been asked with a 12-week endpoint. A three-arm study — 25 mg daily, 100 mg twice weekly, placebo — with flow-mediated dilation and IIEF at baseline and 12 weeks would answer it.
Nobody has characterized the 12-to-70-minute onset spread. Eardley 2002 found a nearly six-fold range in time to onset across 17 men and did not explain it. Gastric emptying, CYP3A4 phenotype, body composition and baseline vascular status are all candidates, and none has been tested against onset time. Somebody who takes this drug and waits 70 minutes each time is being told by their own physiology something the literature has never bothered to characterize.
Sildenafil — its own safety story, not its class's
The nitrate rule is absolute, and here is the size of it. Sildenafil is contraindicated in anyone using nitric oxide donors, organic nitrates or organic nitrites in any form US Food and Drug Administration 2014. Webb 1999 measured what happens: healthy men on 25 mg three times daily for four days, then challenged with intravenous glyceryl trinitrate, dropped systolic pressure by more than 25 mmHg (p < 0.01), and the fall after a sublingual 500 µg nitrate tablet was four times greater during sildenafil than without it. Webb 2000 repeated the point in men with stable angina on nitric oxide donor drugs. This is not an interaction to manage with spacing; the practical danger is the man who takes sildenafil, develops chest pain, and is given sublingual nitrate by a paramedic who was never told. Anyone using this drug should be able to say so under those circumstances.
Alpha-blockers and other antihypertensives are additive but survivable, and the numbers are on the label. With doxazosin, 25 mg of sildenafil produced placebo-subtracted falls of 7.4 mmHg supine and 6.0 mmHg standing US Food and Drug Administration 2014. With amlodipine, Webb 1999 measured −8 mmHg systolic and −7 mmHg diastolic against placebo plus amlodipine (p ≤ 0.002), with heart rate up 2.1 beats per minute versus down 1.5. Those are manageable numbers in a well-hydrated person and they are not manageable stacked with dehydration, alcohol and a hot room.
The two rare irreversible events, and what they look like. NAION — non-arteritic anterior ischemic optic neuropathy — presents as sudden loss of vision in one or both eyes and has been reported post-marketing with all PDE5 inhibitors US Food and Drug Administration 2014. Sudden decrease or loss of hearing has been reported the same way. Both are stop-the-drug-and-be-seen-today events, and both are different in kind from the blue tinge, which is transient, dose-related and benign. Confusing the benign visual effect with the dangerous one is the common error: color change is PDE6 and fades; sudden loss of vision in one eye is not PDE6 and does not.
Priapism. Erections beyond 4 hours, and painful erections beyond 6 hours, have been reported since approval US Food and Drug Administration 2014. Six hours of ischemic priapism causes permanent damage. This is the one adverse effect where the correct action is an emergency department, and the risk is concentrated in sickle cell disease, myeloma, leukemia and anyone stacking with intracavernosal agents.
The dose-adjustment triangle nobody applies to themselves. The label says to consider starting at 25 mg in severe renal impairment, in any degree of hepatic impairment, and over age 65 — where AUC runs 84% to 107% higher US Food and Drug Administration 2014. The common real-world pattern is the reverse: the older man with the more resistant problem takes 100 mg, which is where the headache (28%), flushing (18%), dyspepsia (17%) and abnormal vision (11%) rates on the label were measured. Most of what people call “not tolerating sildenafil” is a starting-dose decision, not a drug incompatibility.
Sources read for this page
- Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM, Osterloh IH, Gingell C. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction.. Int J Impot Res 1996 · PMID 8858389
- Wallis RM. The pharmacology of sildenafil, a novel and selective inhibitor of phosphodiesterase (PDE) type 5.. Nihon Yakurigaku Zasshi 1999 · PMID 10629850
- Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group.. N Engl J Med 1998 · PMID 9580646
- Nichols DJ, Muirhead GJ, Harness JA. Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality.. Br J Clin Pharmacol 2002 · PMID 11879254
- Hyland R, Roe EG, Jones BC. Identification of the cytochrome P450 enzymes involved in the N-demethylation of sildenafil.. Br J Clin Pharmacol 2001 · PMID 11298070
- Webb DJ, Freestone S, Allen MJ, Muirhead GJ. Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist.. Am J Cardiol 1999 · PMID 10078539
- Webb DJ, Muirhead GJ, Wulff M, Sutton JA, Levi R, Dinsmore WW. Sildenafil citrate potentiates the hypotensive effects of nitric oxide donor drugs in male patients with stable angina.. J Am Coll Cardiol 2000 · PMID 10898408
- Eardley I, Ellis P, Boolell M. Onset and duration of action of sildenafil for the treatment of erectile dysfunction.. Br J Clin Pharmacol 2002 · PMID 11879261
- US Food and Drug Administration. VIAGRA (sildenafil citrate) tablets, for oral use - full prescribing information.. FDA approved labeling, revision 2014
Sildenafil — safety, predicted from mechanism
Predicted from mechanism, not from a human safety trial. How that reasoning works →
What the mechanism predicts
Derived from the molecule, not a trial.
- These inhibit phosphodiesterase type 5, so cGMP persists and smooth muscle relaxes — vasodilation. The predicted problems are all the same effect in the wrong place: headache, flushing, nasal congestion and a fall in blood pressure.
- Tadalafil's long half-life (~17.5 h) means its effects — good and bad — persist far longer than sildenafil's. That is why daily low-dose tadalafil exists and why a mistake with it lasts longer.
What has actually been reported
- Extremely well characterized — these are among the most-prescribed drugs in the world. Headache, flushing, dyspepsia and nasal congestion are common and dose-dependent.
- Rare but serious: sudden hearing loss, and non-arteritic anterior ischemic optic neuropathy (NAION) — sudden painless vision loss in one eye. Both are reasons to stop immediately and seek care.
- Priapism — an erection lasting over four hours — is a medical emergency, not something to wait out. Delay causes permanent damage.
How to reduce the risk
Same mechanism as the prediction.
- Start at the low end. The dose-response for side effects is steeper than for benefit.
- Alcohol and these both lower blood pressure; the combination is the usual cause of feeling awful on a normal dose.
What it does to your bloodwork
A fact about the assay.
- Nothing routine. Blood pressure is the measurement that matters and it is not a lab.
Don't run this if
- You take any nitrate — including recreational 'poppers' (amyl nitrite). The combination causes a catastrophic drop in blood pressure and is the one genuinely lethal interaction in this class.
- You take an alpha-blocker, without a prescriber managing the timing.
- You have significant cardiovascular disease or have been advised against sexual activity for cardiac reasons.
Not medical advice. If you take prescription medication or have a diagnosed condition, check this with a pharmacist or doctor.
Sildenafil — interference & stacking
Predicted from mechanism, not from an interaction study. How mechanism-predicted claims are made →
What Sildenafil moves on your bloodwork
Expected direction, not a measured one.
- Complete Blood Count (CBC) with Differential — ↑ expected to rise
Hematocrit and hemoglobin rise — androgens stimulate erythropoiesis. This is the most reliably predictable movement of any compound in the Vault.
What to do: This is the number that decides whether you keep going. Baseline and every 3 months. Dehydration on the draw day inflates it, so hydrate normally or you will chase a false reading. - Total Testosterone — ↑ expected to rise
Expected. Trough vs peak matters enormously — the same protocol reads completely differently depending on when you drew.
What to do: Draw at the same point in the cycle every time or the trend is noise. - LH & FSH — ↓ expected to fall
Suppressed by negative feedback. This is the mechanism, not a side effect — and it is why exogenous androgen shuts down your own production.
What to do: Relevant if fertility matters to you. Worth knowing before, not after. - Estradiol, Sensitive (LC/MS-MS) — ↑ expected to rise
Aromatization converts a fraction to estradiol, and it rises with the androgen. Use the sensitive (LC-MS/MS) assay — the standard immunoassay is unreliable in men and produces numbers people then medicate.
What to do: If you are reading estradiol in a man, the assay choice matters more than the result. - SHBG (Sex Hormone-Binding Globulin) — ↓ expected to fall
Falls with androgen exposure, which raises the free fraction — so free testosterone can climb faster than total.
What to do: Read total and SHBG together; total alone understates what changed. - Lipid Panel (Cholesterol, HDL, LDL, Triglycerides) — ↓ expected to worsen
HDL falls, sometimes markedly. Oral 17-alpha-alkylated compounds do this far more aggressively than injectable esters.
What to do: Baseline and 12 weeks. ApoB is the better long-term read than LDL-C. - PSA (Total + Free + % Free) — ↑ expected to rise
Androgens can raise PSA modestly. It does not create prostate cancer that wasn't there, but it can unmask it.
What to do: Baseline before starting matters — without it, a later number has nothing to be compared against.
- How to work up to it, and when not to
- When to take it, and why that window
- Cycle length
- Time off between cycles
- Fasted or fed, and when in the day
- Coach Cam's personal notes
- Which compounds push the same lever, and why the dose adds up faster than people count
- What blunts it — the stacks that waste your money
- What compounds the risk, so a side effect arrives sooner than any one of them suggests
- Coach Cam's read on running it alongside the rest of your protocol
Everything above is free and stays free. Skool is where it becomes a plan — Sildenafil in an order, with the rest of what you're running.
Unlock in Skool — $10/mo →Bloodwork to run alongside Sildenafil
Baseline first, then again at 8–12 weeks.
| Marker | What it’s watching for |
|---|---|
| Total Testosterone | The baseline you can't reconstruct later |
| Free Testosterone | The fraction that does anything — total alone misleads |
| SHBG (Sex Hormone-Binding Globulin) | Explains a normal total sitting on top of a low free |
| Estradiol, Sensitive (LC/MS-MS) | The other half of the ratio, and the source of most symptoms |
| LH & FSH | Separates a testicular problem from a pituitary one |
The “Low T? Rule Out the Reversible Causes First” panel covers these in one order — 11 markers, $211.50 with the discount applied.
Check results you already have → · All 103 markers A–Z
Sildenafil — frequently asked questions
What is Sildenafil?
Sildenafil (Viagra) is a hormonal & sexual research compound. PDE5 inhibitor, same target as tadalafil but far shorter acting and more selective for PDE5 over PDE11 — which is why it causes less back and muscle ache and more visual disturbance (PDE6 crossover).
Is the full Sildenafil protocol on this page?
The reported research dose is on this page, along with how Sildenafil works and the evidence behind it. The protocol — how to work up to it, frequency, cycle length, time off, what not to stack it with and Coach Cam's notes — is inside Skool.
What is the half-life of Sildenafil?
Sildenafil has an approximate half-life of ~4 hours, which is part of what determines how often it's dosed.
What's the evidence behind Sildenafil?
Current evidence level: The original PDE5 randomized-trial dataset. Sildenafil is offered for research purposes only and is not an approved medicine.
What Sildenafil is used for
Sildenafil appears under 1 goal in the goal router.
Related Hormonal & Sexual compounds
Where this goes next
The pages here are the frameworks. The protocols — the dosing, the order to correct things in, the week-by-week schedule and what to retest — are inside Skool.