This movie is totally misunderstood by literally everyone... Everything in this movie is a complete (and a fantastic) analogy to drug addiction, and how becoming delusional affects your sense of reality. Greg lost his perception of what's real, started imagining things that didn't happen, and started to think that he is living in a simulation. His high (or "bliss")-state started becoming his new reality, and actual reality started to feel like a simulation to him - at some point he was convinced that the real world was fake.
From the very beginning, we can see that he has a very vivid imagination (and a lot of those imaginations came back later, as he imagined them to be reality while high on crystal-meth).
Greg lost his job at the beginning of the movie. This caused him to disassociate, and combined with the high had after snorting his prescription medicine at the beginning of the movie, he started imagining things, starting with his first delusion that he killed his boss.
Then, he went from fired to homeless and was introduced to crystal meth. The "crystals" in the movie are probably a reference to crystal meth.
Now, Isabel, she's literally a personified representation of addiction itself, and whether she's real or one of his imaginations can be up for debate.
As we know from the very beginning of the movie, he was obsessed with some dream-house/wife. Through his addiction to crystal meth, his highs let him live in that house and be with that girl of his dreams, in his imaginated world.
The "permanent escape" at the end of the movie was obviously referring to an overdose - suicide.. but he ended up chosing his own life over Isabel's (IOW, he choose reality over addition). So, instead of killing himself, he killed his addiction and decided to go to rehab.
His daughter in this movie was obviously real, and in the end, she's the one that grounded him to reality, and this practically saved him this way.
Rewatch the movie with THIS perspective and you'll appreciate this masterpiece!!!!