A bit of an obscure bit of knowledge here, but they are MUCH harder to knock out if in the presence of insects. I knocked out the same Megatherium twice, the first time I knocked it out I was hovering over it with my Rhyniognatha, and it took a long time and many tranq arrows.

I then knocked it out a second time while it was in a trap with no insects in sight, and it went out fairly quickly.

If you a trying to knock out a megatherium and it’s taking suspiciously long, make sure there are no insects in the area, be they wild or tamed