So the movie "Fatal Beauty" would have been spec? That had a made-up drug as well (along with bad acting and horrible chemistry between the MCs, but that's a whole other issue, lol). Now if the drug did more than hallucinations, a la "Limitless" where it made the user super-intelligent, I'd be on board. But I'm not sure that simply having a fictional drug per se classifies something as speculative.
Maybe I'm wrong, but I'm basing it of my understanding of the spec label: an umbrella term for fantasy, sci-fi, horror, etc. From the (admittedly) few editors I've talked to about it, that's their take on it, too.
I think Lisa does have an arguement for spec with the boy who does/doesn't exist. But I'd personally hesitate to go to agents specializing in sci-fi and fantasy if I made up a new hallucinogen, but absolutely everything else was "real" world in the story.
And yeah, TMCan, I'd definitely classify that as speculative. But as Polenth said, where it's shelved would be another matter. Technically Crichton wrote spec/sci-fi, but I've rarely found his books shelved there.