You may or may not know that the original Blue Velvet script specified that Frank Booth (Dennis Hopper) frequently inhaled helium, giving him a high-pitched voice resembling that of an infant:
Dorothy looks up at the ceiling, waiting. Frank suddenly reaches to his belt, where he has a small canister and a mask. He opens a valve on the canister and places the mask over his nose and mouth. The canister is filled with helium, which makes Frank’s voice very high and strange sounding. The result is frightening.
However, Frank Booth’s Wikipedia page describes that Hopper, an experienced drug user, claimed to have insight into Booth’s choice of drug, and said that helium was inappropriate. David Lynch commented on the sudden change:
I’m thankful to Dennis, because up until the last minute it was gonna be helium — to make the difference between ‘Daddy’ and the baby that much more. But I didn’t want it to be funny. So helium went out the window and became just a gas. Then, in the first rehearsal, Dennis said, ‘David, I know what’s in these different canisters.’ And I said, ‘Thank God, Dennis, that you know that!’ And he named all the gases.
Booth’s gas of choice turned out to be amyl nitrite, a medication for heart disease, angina and cyanide poisoning which is also used recreationally as an inhalant that induces a brief euphoric state. Though if you wonder how he would’ve sounded on helium, here’s a video that gives you an idea. What do you think, creepier or not?
Warning: this clip contains violence, strong language and sexual behavior. Definitely NSFW.
(Compare to the original scene here)
Blue Velvet, the 25th Anniversary Edition is now available on Blu-ray.
Fire walk with 
I always assumed it was nitrous oxide.
It was nitrous. Helium makes no sense and would change the voice pitch to Donald Duck.
The first paragraph above says that the original script had Frank inhaling helium, not the actual movie script stated that. Presumably, whoever wrote the original script was not a recreational drug user, since helium isn’t a recreational drug, unless you consider that making your voice sound high is recreational.
In the movie “Blue Velvet,” Frank Booth, played by Dennis Hopper, is shown inhaling amyl nitrite, also known as “poppers.” Amyl nitrite is a volatile liquid that vaporizes at room temperature, and inhaling its fumes can produce a brief but intense psychoactive effect, often associated with a head rush or heightened sensations. It’s worth noting that the portrayal of drug use in the film is part of its depiction of the dark and disturbing aspects of the characters and their world.