Black Triad: three drugs in one tablet, and the trial that never ran

The Black Triad tablet carries three of this catalogue’s best-documented molecules in one film: two PDE5 inhibitors and one SSRI, the sildenafil and tadalafil of the erectile-dysfunction range with the dapoxetine of the premature-ejaculation range. Each of the three has a substantial randomised file. The tablet that combines them has none, and the reason is worth a page because the reasoning that leads people to buy it is so widely repeated and so quietly unevidenced.

What the big reviews actually pooled

The 2015 Sheffield assessment screened 103 studies, 102 of them randomised controlled trials, on premature ejaculation, using intravaginal ejaculatory latency time as the primary outcome and meta-analysing where possible. The interventions that significantly improved IELT against placebo were: topical anaesthetics; SSRIs including citalopram, escitalopram, fluoxetine, paroxetine, sertraline and dapoxetine at 30 mg and 60 mg; duloxetine; inhaled clomipramine 4 mg; the PDE5 inhibitors vardenafil and tadalafil; and tramadol.

Every entry on that list is a single agent. The two PDE5 inhibitors in that list are exactly the two that appear in this tablet, and they appear as monotherapies against placebo — not stacked on each other, and not stacked on an SSRI.

The 2018 network meta-analysis pooled 44 randomised trials and ranked them. Dapoxetine 30 mg had the highest likelihood of being the best available agent, which is why it anchors the discussion. The combination arms in that network are informative too: dapoxetine 30 mg with mirodenafil, paroxetine with sildenafil, topical lidocaine with tadalafil, paroxetine with tadalafil, combined fluoxetine with tadalafil. Three-drug stacks are absent. Two-drug stacks are present for some pairs and absent for others.

What the guidelines say about combining them

The 2013 ISSM standards of care grade their own evidence on a scale, and the combinations sit at the bottom of it. Level 1 covers PDE5 inhibitor monotherapy and injectable or intraurethral prostaglandin E1. Level 3 covers combining a PDE5 inhibitor with injection therapy, which “generate better efficacy rates than either monotherapy alone”. Level 5 is expert opinion, and that is where PDE5 inhibitor plus dapoxetine is placed, on the grounds that the combination “is effective and safe in patients suffering from both ED and premature ejaculation”.

Nothing in that document describes a trial for the two-PDE5-inhibitor-plus-SSRI stack. It is expert opinion about a two-drug combination, and this product is a three-drug one.

What has been measured about stacking two PDE5 inhibitors

Here the honest answer is that the indexed literature is quiet. The one study in this file that physically combined a PDE5 inhibitor with dapoxetine is the 2018 pharmaceutics paper on dual-purpose vardenafil and dapoxetine orodispersible tablets — freeze-dried for dissolution, with gelatin as matrix former and N-methylpyrrolidone as solubiliser releasing 100 % of both drugs within 15 minutes. Its in vivo arm was six healthy male volunteers, reporting a vardenafil Tmax of 0.583 ± 0.129 h and a dapoxetine Tmax of 0.625 ± 0.137 h, and relative bioavailability of 100.9 % and 85 % against Levitra and Priligy.

Six volunteers, two drugs, pharmacokinetics. No IELT, no placebo, no efficacy endpoint, and nothing at all on combining two PDE5 inhibitors with each other.

That silence matters pharmacologically. Both sildenafil and tadalafil inhibit PDE5 through the same mechanism and are cleared with overlapping pathways; stacking two members of one class is a different proposition from combining a PDE5 inhibitor with an SSRI that acts on serotonin reuptake. The literature cited above does not address it, and this page does not speculate about it beyond saying what is absent.

The quality-control angle is the one with data

The remaining indexed paper in this file is an analytical one, and it is not irrelevant. The 2021 RSC Advances study built HPLC-UV and UPLC-MS/MS methods to determine sildenafil, vardenafil and tadalafil alongside the compounds commonly found in counterfeit aphrodisiac products — dapoxetine, paroxetine, citalopram, tramadol and yohimbine — and applied them to 50 commercial products including honey sachets and instant coffee marketed as aphrodisiacs.

A tablet containing three actives in film form is exactly the kind of object that needs that method to verify what is inside it, which is why purity documentation for research peptides and combination tablets belongs on the same page as the pharmacology. It is a measurement the field can do, on a real product, in a way that an IELT claim cannot be measured at all.

What the data do not show

• No placebo-controlled trial of a three-drug stack exists. Not in the 103 studies of the Sheffield assessment, not in the 44 randomised trials of the network meta-analysis.
• No trial measures this tablet’s effect on IELT, on erection, or on either outcome versus its own components.
• Guideline support for a two-drug combination is level 5 — expert opinion. A three-drug stack is not discussed at all.
• Stacked PDE5 inhibition is not studied in the sources above. The absence is real and is not evidence of safety.
• Nothing here is advice. The milligrammes in these papers are the regimens those studies ran; nothing supplied here is a treatment for a diagnosed condition, and no statement on this page recommends taking any combination.

For the two-member comparison the field does have trials for, see sildenafil against tadalafil.