ITPP: Can You Run Cardarine & ITPP Together?

TL:DR it’s not clear, but the broscience of not running ITPP & Cardarine together has merit.

I was part of an interesting discussion recently regarding Cardarine & ITPP not providing a benefit when ran together, based off a single anecdote. The story goes that the user noticed no cardio/endurance benefit when running both compounds together, but when they discontinued ITPP and continued the Cardarine by itself their endurance shot up.

As usual, we don’t have any direct studies testing this exact scenario. There is one important method of action in which these compounds do cause opposite effects which we’re going to look at - angiogenesis.

What is angiogenesis?

Angiogenesis refers to the creation of new blood vessels (angio relating to blood/circulation, and genesis relating to creation). As this relates to our two compounds in question ITPP is antiangiogenic while Cardarine is angiogenic.

ITPP: When RBCs are loaded with ITPP, endothelial cells (ECs) do not align, i.e., do not form “vessel”-like structures, because the “loaded” RBCs are capable of releasing under hypoxia more oxygen than their “normal” counterparts. [2]

Cardarine: activation of PPARβ/δ induces angiogenesis, in vitro and in vivo

(Note that there is some data that indicates the opposite is true of cardarine as well, depending on dose and the kind of cell being dosed. PPARδ agonists seem to have pro-angiogenic activity at very low concentrations… [Yet at high doses] We found that treatment with PPARδ agonists inhibited the formation of capillary-like structures and endothelial cell migration.)

Between the two compounds there are opposing and contradictory MOA at work which might help explain my bros experience - angiogenesis should increase endurance, and pairing it with a compound that prevents it could reduce the benefit of Cardarine.

What else could cause this?

The method of action for both compounds is rather different. That is to say, if running Cardarine & ITPP are somehow detrimental to performance, and it’s not because of the different effects on angiogenesis, it could be anything.

Quick recap on their MoA:

ITPP: decreases the oxygen binding affinity of Hb (hemoglobin), increases tissue oxygen delivery… thus (is) an attractive candidate for the therapy of patients with reduced exercise capacity (or folks like us wanting to run further, and go longer)

Cardarine: increase(s) skeletal muscle fatty acid catabolism. The targeted activation of PPARdelta in adipose tissue specifically induces expression of genes required for fatty acid oxidation and energy dissipation.

If you have thoughts on how these two MoA might otherwise conflict with each other, would love to here your theory, be it broscience or a legit hypothesis.

So what?

n=1 is not an appropriate sample size to draw conclusions from anecdotes, but based on how Cardarine induces angiogenesis and ITPP prevents the forming of new blood vessels I wouldn’t recommend running the two together. At best, it’s not going to be as effective as you would hope. More data / bro-dotes are needed.