This episode was originally registered under the title "Episode 420", although the final record shortens it to simply "420". The DVDs and most media use the original title.
420 is a very recognized number in pot culture, and some pot smokers actually take it so seriously as to specifically smoke at the time of 4:20, as well as celebrate a holiday on April 20th (04/20). This episode originally aired one day before that holiday.
When Peter's siren song is the theme from The Rockford Files.
Peter Griffin produces a clip against smoking marijuana in which he mentions Harold and Kumar Go To White Castle, a 2004 stoner comedy film, and Neil Patrick Harris's role in the film. He then talks about How I Met Your Mother a sitcom in which Neil Patrick Harris stars. He then trails off into comments regarding Josh Radnor and Bob Saget and claims he can't understand how Ted Mosby, played by Josh Radnor grows up to become, Bob Saget, when Ted is already an adult.
The song "A Bag of Weed" is set to the tune of "Me Ol' Bam-boo" from the 1968 musical film, Chitty Chitty Bang Bang.
This is the first episode where Diane did not wear her shirt and coat again for the second time. It is revealing she is wearing a singlet or a one-piece swimsuit for her underwear. She did have her coat off in "Brian: Portrait of a Dog".
Brian said that the legalization of cannabis had led to an increase in ratings for Doctor Who. This is in regards to the video effects used in the title sequence of episodes from the early years of the series which used various video feedback techniques such as "howlaround" from 1963 to 1973 and "Slit-scan" from 1973 to 1980  to achieve what some describe as a psychedelic effect.
The broadcast order for episodes "420" through "Peter's Progress" were altered in the UK due to Michael Jackson's death. This episode was aired 67 days before Michael Jackson died, excluding the day of his death.
In this episode, Lois is dead-set against Brian's pot usage. But in "Barely Legal", she gave him a bag to help him cope with taking Meg to the dance.