Erectile dysfunction (ED) occurs in younger men under 40 years of age in only 1–10% of the population, where a suggestive sign of ED is a low testosterone (TST) level. In men over 40, ED becomes more prominent and, over the age of 70, 50–100% of men have issues with it. In men using AAS, the biggest problems with ED arise after a steroid cycle, although ED can sometimes appear during a cycle as well, for example when using Nandrolone.
It’s of course clear that androgens play a role in erectile function because they influence the nervous system as well as the relevant tissues of the sexual organs. But the role of androgens is often unnecessarily overestimated in this respect, because when hypogonadal men with ED are given testosterone, results show only very small improvements in ED. It’s important to realise that multiple factors impact ED, and one of the most common is the psychological factor, which most men do not want to admit. We distinguish three types of ED:
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Psychological (performance anxiety, relationship issues, stress, depression …)
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Organic (neurogenic, hormonal, arterial, cavernosal, drug-induced …)
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Or psychogenic-organic (mixed)
If a man has nocturnal and morning erections, the cause of his ED is very likely psychological. An erection is essentially the result of trapping blood in the penis. Smooth muscle in the penis restricts blood flow into its tissues, but with sexual stimulation the smooth muscle relaxes, blood flow increases, and venous outflow is automatically reduced. An erection is thus achieved by a combination of increased inflow and decreased outflow of blood. Relaxation of the smooth muscle occurs mainly via the enzyme phosphodiesterase-5 (PDE5) and it is precisely by inhibiting PDE5 that ED can be treated—the profiles of these medicines are given below in the article.
I would also like to mention medicines that can negatively affect erections:
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Selective serotonin reuptake inhibitors (SSRIs)
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Thiazide diuretics
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Beta-blockers
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H2 antagonists
Marijuana, opiates and cocaine also have a negative impact on erections, as does obesity.
The substances mentioned in the title of this article (Sildenafil, Tadalafil and Vardenafil) are phosphodiesterase type-5 inhibitors (PDE5 inhibitors). All PDE5 agents have essentially the same mechanism and are used to treat erectile dysfunction (impotence) in men; they mainly differ by half-life. These medicines block the PDE5 enzyme, which breaks down cyclic guanosine monophosphate (cGMP) in penile tissue. By doing so, they help improve blood flow upon sexual arousal and thus help achieve and maintain an erection. When a man is sexually stimulated, nitric oxide (NO) is released in the penile tissues, which triggers the production of cGMP; cGMP dilates penile blood vessels, the penis fills with blood and an erection occurs. So the more cGMP, the better the perfusion and the stronger the erection—and vice versa. As noted, when PDE5 is active it degrades cGMP, lowering its level. This causes smooth muscle contraction in vessel walls, narrowing them and reducing blood flow; if PDE5 is inhibited by PDE5 inhibitors, the opposite occurs.
All these agents are therefore vasodilators, as they relax blood vessels to increase blood flow. They can also increase blood flow in the lungs, which can lower blood pressure in the arteries supplying the lungs.
Like other agents, PDE-5 inhibitors have effects on other enzymes too; they also inhibit PDE-6 to varying degrees, which is present in the retina and is involved in vision, playing a key role in transmitting light and neural signals. Thus, during use of PDE-5 inhibitors, colour-vision issues can occur. Sildenafil and Vardenafil are only about 3–7× more selective for PDE-5 over PDE-6, whereas Tadalafil is ~700× more selective, meaning Tadalafil affects PDE-5 versus PDE-6 at a ratio of 700:1, making vision disturbances much less likely. So yes, Sildenafil and Vardenafil have a certain degree of off-target activity on PDE-6, which can result in visual disturbances. Tadalafil has minimal activity on PDE-6, but more pronounced activity on PDE-11, expressed in skeletal muscle—likely the reason for the back pain reported with Tadalafil use.
The effectiveness of Sildenafil and Vardenafil is tightly linked to diet: dietary fat slows and reduces their absorption. Interestingly, Tadalafil is much less affected by food—you can take it with food, before or after; it doesn’t meaningfully affect its action.
Sildenafil (Viagra) was originally studied for hypertension, but it was found to improve erections. In 1998 it was approved by the FDA to treat ED in men. It has also been shown to likely enhance athletic performance and to raise testosterone levels. Many also use it to increase muscle pump during training, as Sildenafil is a strong vasodilator. Facts from studies: Matthew Spitzer investigated Sildenafil’s effects in 140 men with low testosterone. Sildenafil doses varied: men on alpha-blockers received 25 mg; Sildenafil-naïve men received 50 mg; experienced users received 100 mg. Hormonal profiles were tracked for 3–7 weeks. On average, total T increased by ~40% and free T by ~50%, with DHT also rising. It’s also documented to increase exercise capacity by improving pulmonary blood flow and oxygenation during endurance training/competition. For bodybuilders, the more relevant point is the increased pump/vascularity due to vasodilation.
Tadalafil (Cialis) was studied by Eli Lilly starting in 1998 and approved in 2003. In medicine it’s used for:
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Treatment of erectile dysfunction
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Treatment of pulmonary arterial hypertension
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Treatment of signs and symptoms of benign prostatic hyperplasia (BPH)
Many take it throughout a cycle in low doses every day or every other day (2.5–5 mg). Such low doses bring minimal side effects but can help reduce blood pressure, increase pump during workouts and have favourable effects on the prostate and erections. Such low Tadalafil doses can also be used in PCT to boost endogenous testosterone and improve erectile capacity via vasodilation.
In practice, 5 mg daily is common; thanks to the long half-life, daily 5 mg accumulates to an effect similar to a single 10 mg dose, but with fewer adverse effects—supported by a study using 5 mg daily for up to 24 weeks, which also showed its efficacy did not wane.
Tadalafil is officially used to treat symptoms associated with BPH (urinary issues, increased frequency, weaker stream). It relaxes muscles in the prostate and bladder, making urination easier. Note: Tadalafil does not shrink the prostate—it only alleviates BPH symptoms. Therapeutic dosing here is 5–10 mg daily.
Tadalafil also shows selectivity for PDE-11, concentrated in the prostate, testes and skeletal muscle. Inhibition of PDE-11 is associated with muscle pain, hence the characteristic back pain some users report—usually mild to moderate and lasting 12–48 hours after dosing.
Another interesting point: Tadalafil often brings mild to moderate reductions in oestrogen (E2); there are some study records on this, including in women. Reports from TRT users on low-dose Tadalafil (2.5 or 5–10 mg daily) also frequently mention decreased E2. This effect does not occur in everyone and the reason isn’t clear. One study: 20 men, mean age 54, took 10–20 mg Tadalafil on demand for 12 months. Findings:
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E2 fell from 19.9 to 16.6 ng/dl
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T/E2 ratio increased
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Total T rose slightly from 411.4 to 434.2 ng/dl
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Free T rose slightly from 47.7 to 49.9 ng/dl
Interestingly, the E2 drop correlated with body weight—E2 decreased in lean men, not in obese men. Another in-vitro study found Tadalafil modulates aromatase activity and androgen receptor expression.
Vardenafil is, per studies, more potent than Sildenafil, but less known. Most people think first of Viagra (Sildenafil) when it comes to ED drugs and therefore search for it; few search for Vardenafil and many don’t know it at all.
Differences in pharmacodynamics (half-life, duration of effect, etc.)
Sildenafil citrate
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its half-life = approx. 4 hours
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the effect can be perceived throughout the day with a gradual decline after the first 4 hours from ingestion
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onset of effect = 30 to 60 minutes after ingestion, full effect occurs only after 60–90 minutes
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dosage for improvement of sexual performance = 25 to 150 mg
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must be taken on an empty stomach
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in studies, sildenafil increased the duration of erection by 60%
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in men with diabetes, the effectiveness of Sildenafil decreases by 40 to 60%
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its bioavailability is 41%
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maximum blood concentration is reached approximately 0.5 to 2 hours after administration, with an average of 1 hour
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taking Sildenafil with a high-fat meal reduces blood levels of this substance by 29% and the onset of effect is delayed by about 60 minutes; on an empty stomach, it reaches maximum plasma concentration in about 1 hour, but after a high-fat meal only after 2 hours
Tadalafil citrate
- its half-life is about 17.5 hours
- the effect can be perceived even 2–3 days
- onset of effect 30–60 minutes, full effect occurs only after several hours
- dosage for improvement of sexual performance = 10 to 40 mg
- maximum plasma values are reached approximately 2 hours after ingestion
- it can be taken with food, on an empty stomach or after a meal
- its bioavailability is 80%
- maximum blood concentration is reached between 0.5 to 6 hours after administration, with an average of 2 hours
- taking Tadalafil with a high-fat meal has no effect on blood levels of this drug, which is very positive; in fact, the truth is that the maximum achieved plasma levels are on average after 2 hours, and after a meal with high fat content, the maximum level was reached after 2.5 hours
Vardenafil hydrochloride
- its half-life = approx. 5 hours
- the effect can be perceived throughout the day with a gradual decline after the first 4 hours
- onset of effect = 15 to 30 minutes after ingestion, full effect occurs only after 60–90 minutes
- dosage for improvement of sexual performance = 5 to 20 mg
- must be taken on an empty stomach
- its bioavailability is 15%
- maximum blood concentration is reached 0.5 to 2.5 hours after ingestion, with an average of 1 hour
- taking Vardenafil with a high-fat meal reduces blood levels of this substance by 18 to 50%; in the study, as with Sildenafil, maximum plasma levels were reached after about 1 hour, but after a meal with high fat content only after 2 hours
- what is also quite interesting about Vardenafil is that when Vardenafil was taken with water, the onset of its effect was very rapid and its maximum blood levels were always achieved significantly earlier. This means that Vardenafil should not be taken with too much water
As you can see above, maximum plasma levels can be reached by ~30 minutes with Sildenafil and Vardenafil, whereas for Tadalafil the average is ~2 hours—this aligns with the faster onset for Sildenafil/Vardenafil and slower for Tadalafil. Still, all are generally recommended to be taken at least 1 hour before sexual activity.
Adverse effects with PDE5 inhibitors
All of the side effects listed below are usually observed at a dose of 100 mg of Sildenafil, 20 mg of Vardenafil, or 20 mg of Tadalafil. However, beginner doses for most of you will be much lower, and therefore the manifestation of adverse effects will be significantly lower, especially at doses of 25 to 50 mg of Sildenafil, 5 to 10 mg of Tadalafil, or 5 to 10 mg of Vardenafil. You may think these are low doses, but in most cases they will be sufficient.
• Headaches, which can be intense and unpleasant for many
• Nasal congestion, which can be very easily treated with a decongestant (a nasal spray commonly used for colds)
• Red eyes, tearing, for which ordinary eye drops such as Visine and many others can help. In some users, swelling of the eyelids has also been reported
• Ocular pressure
• Vision problems, blurred vision, light sensitivity, and seeing objects with a bluish tint
• Ringing in the ears (tinnitus)
• Dyspepsia (reflux, which is most commonly reported with Tadalafil)
• Facial flushing, a hot face, palms, and basically the whole body. In fact, the more intense and the longer the flushing lasts, the greater the likelihood of headaches
• Increased blood pressure – paradoxically, in the first hour, maybe two, your blood pressure will start to rise and then it should drop, which is a fairly sought-after effect among people using AAS who have problems with blood pressure. In studies, only a mild decrease in blood pressure is observed through the effect of PDE5 inhibitors. What you need to be careful about, however, is using PDE5 inhibitors together with blood pressure medications, as this can lead to hypotension, i.e. excessively low blood pressure
• Priapism, a condition in which an erection lasts too long and is painful. In such a case, medical help is necessary. This side effect is very rare, and personally, I have never heard of anyone in my surroundings who experienced it
• Heart attack – these substances can affect the cardiovascular system and increase the risk of heart problems, especially in people with pre-existing cardiovascular diseases
• They can induce ventricular arrhythmias (irregular heart rhythm), which is quite an uncommon phenomenon, but heart palpitations are also frequently reported
• Stroke – essentially the same as with heart attack, here too blood circulation can be affected and the risk of stroke increased, especially in people with existing risk factors
• Sudden but temporary hearing loss – this is a very rare phenomenon, but it does happen that some men report sudden hearing impairment
• Sudden and temporary vision loss has been reported several times, and thus very rarely, during the use of PDE5 inhibitors. These are cases of non-arteritic anterior ischemic optic neuropathy, a condition in which blood flow to the optic nerve is blocked. Diabetics and people with high blood pressure should especially be careful about this phenomenon.
Desired effects with PDE5 inhibitors
• Improvement of erections and sexual performance
• Reduction of blood pressure (especially with Tadalafil)
• Better muscle pump during workouts
• More pronounced vascularity throughout the day
• Increased production of endogenous testosterone during PCT
• Positive effect on the prostate (Tadalafil)
• Studies show they have a mild positive effect on cholesterol, slightly increasing HDL levels and improving the HDL to LDL ratio. In some studies, they had no effect on cholesterol, and in others only a very mild positive effect. The key point is that a significantly negative effect on cholesterol has never been reported.
Quite often on various forums, the topic of muscle growth during the use of PDE5 inhibitors is discussed, especially in connection with Tadalafil. To this day, there is no evidence that these substances can directly increase muscle growth. Yes, it is true that PDE5 inhibitors promote a stronger pump during workouts, which leads to stretching of the fascia, and this may have a very, very minimal positive effect on muscle growth.
Using PDE5 inhibitors together with recreational drugs
Is it possible to use them together? What impact can the use of PDE5 inhibitors combined with drugs have on cardiovascular aspects? Cocaine causes systemic vasoconstriction = narrowing of blood vessels throughout the body and increases cardiac output (heart rate). This causes the heart to thicken (cardiomyopathy, the heart muscle becomes weaker, stiffer, or enlarged), and unlike athlete’s heart hypertrophy, cocaine-induced cardiac hypertrophy is associated with impaired heart function. The use of cocaine can also trigger severe arrhythmia in many people. Therefore, in the case of using cocaine together with a PDE5 inhibitor, vessel relaxation could occur, which might have a positive effect. What I would be more concerned about is the increased risk of unwanted arrhythmia, especially if cocaine is combined with Sildenafil.
As for ecstasy, which should contain MDMA, in most cases on the black market fake products are sold containing substances far more harmful than relatively safe MDMA if it is “pure.” Therefore, it is quite difficult to comment on the combined use of PDE5 inhibitors with such fake products, in which essentially anything could be present.
Returning to cocaine: if it were used together with Tadalafil or Sildenafil, I would be concerned about priapism = prolonged and painful erection. Cocaine increases sexual desire and also stamina during sexual intercourse, and together with Tadalafil or Sildenafil this could be really interesting. If any of you are going to try this, I would definitely start with low doses and carefully observe what happens with heart rate and blood pressure, and only later try to go into higher doses of both substances.
I am not encouraging anyone here to use drugs, but I have often received this question from various people, so I provided at least this partial answer, but I do not want to go into it more deeply.
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