PokéBase - Pokémon Q&A
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I don’t know if I should run it with +Attack or +Speed nature, and if the held item should be a focus sash, life orb or something else.

And if there’s a way I should run it, such as if it’s worth risking using Psystrike then Selfdestruct or just straight up Kaboom.

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Self-destruct was nerfed pretty badly in Generation 5, so I'm pretty sure self-destruct Mewtwo is good only in earlier games.
sumwun are you sure that it was Explosion that got nerfed and not Selfdestruct?
Holy crap that got nerfed really bad.
To be fair, 400 BP was way OP.
Though I will say that using a move that kills your Mewtwo seems like such a waste, especially when you consider the fact that Mewtwo's mega forms share with mega Rayquaza the highest base stat total of all Pokemon. I'm not saying Self-Destruct Mewtwo is unusable, but there's just so many better ways to take advantage of Mewtwo.

1 Answer

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Selfdestruct and Explosion are usually only used on suicide leads and after they no longer half the defense stat of the target their usage has gone down a lot. Mewtwo doesn’t get STAB from the move, and in most circumstances it won’t do much damage, especially if you’re facing other ubers. You’re likely to end up getting completely walled by something like Lugia or Giratina. it’s a complete waste to kill off Mewtwo as you’d likely want to use it as a fast special sweeper.
If you want a psychic-type lead, go with Speed Deoxys. Mewtwo also faces a lot of competition as an offensive psychic from Necrozma and Attack Deoxys, so consider which one’s best for your team.

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I know this. I’m not trying to use a best psychic type, im just trying to make a jihad joke in competitive battling.
So you want to know whether a self-destruct Mewtwo will be an effective Jihad joke? I'm pretty sure that question is too opinion-based to be allowed here.