The Substance, like so many things, is about Death
It's about gender, consumerism, fame, yes - but human finitude most of all
The Substance - the thing in the film, not the film itself - is a cruel method of suicide. Elizabeth’s life feels to her like it is over, because the identity she had as a star has come to an end. Her life itself could go on, but she tries to hold on to what she cannot hold on to, and so her life ends completely, horribly, violently.
The consequences of taking the Substance are predictable and inevitable. The new hyper-vital version of yourself is spawned from a place of insecurity, self-loathing. Of course the vital part of you will resent the decaying part of you, of course the vital part will accelerate the decay of the decaying part, of course your life will end faster and more miserably than it would had you accepted your shortcomings and limitations.
The limitation that we all have to accept is limitation in general, the metaphysical condition of inevitably being flawed and one day having to die.
Elizabeth didn’t have to die, at least not yet. She could have started over, turning the page and being known as a different person. A sweet middle class man from high school recognizes her on the street and asks her out, taken by her beauty as she is today and seemingly wanting nothing from her as a rich movie star. The relationship he offers her, the person she could be in that relationship, is completely unlike anything she had known or wanted. Of course she does not accept his offer - she would rather keep playing the game of hating herself for familiar insufficiencies than step in to any kind of unknown. She only digs his number out of the trash after running into Sue’s unkind lover on the street and wanting to prove that if Sue can get laid then she can too, the one bid for connection she makes coming from a place of doomed competition.
Gender and fame are the core elements of the story, worthy ones, and the film is confronting and thought provoking along those dimensions. What animates the film at its heart is something that even I as a non-famous man can connect with - what animates the film is Death, self-destruction, and denial.
Elizabeth persists in her Substance use all the way to the bitter end for the same reason so many keep drinking and drugging long after it stops being cute - to stop would mean admitting that we destroyed ourselves for nothing.