It's a lot harder, to be sure. Spiders are deadly in the early stages and The Widow is quite hard if you face her without any tear upgrades.
I can't bring myself to unlock Samson yet because there are so many items I don't want to pass up anything and I'm seeing new items more than half the time. I've beaten it once (with Maggy, surprisingly) thanks to getting Ipecac which makes The Womb/Sheol pretty easy even if it's way harder to use than Dr. Fetus.
I only needed two more items to get Golden God before this and somehow I suspect I just made my odds much, much worse of getting it any time soon.
Bug with the new ending:
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