This episode reveals that Lisa takes Xanax for stress problems.
When Homer, Grandpa, Flanders, and Apu go to Winnipeg a sign can be seen as they enter the city. It reads: "Welcome to Winnipeg. We were born here, what's your excuse?".
The van that Homer, Grandpa, Flanders, and Apu take to Canada appears to be a first-generation Toyota Sienna (1998-2003). It appears to have three doors, and although some Toyota Siennas from 1998-2000 had three doors (lower-level CE trim only), three door Siennas are very rare.
Lisa mentions how the TV series, "Friends," ended and was taken off the air; therefore, this episode must take place no earlier than May 7, 2004, due to the show ending just the day before that (on May 6 of that year).
This is the first episode to air in 2005.
Ironically, with part of the episode taking place in Winnipeg, CKND, the Winnipeg station that airs first-run episodes of The Simpsons, aired an NFL playoff game on January 16, 2005 in place of this episode.
On UK's Sky1 channel, the reference to Krusty the Clown needing lithium to curb his bipolar disorder is cut.
On the Canadian News, Homer is referred to as a former U.S. astronaut, a reference to Deep Space Homer.
Homer being restricted from entering Canada is a reference to the episode Kill the Alligator and Run which involves the whole Simpson family being banned from Florida.
The title is a parody of the film Midnight Express.
The drug store is called "Dudley Do Drugs" a parody of Dudley Do-Right.
Huey Lewis' single "I Want a New Drug" was used in the Pharmaceutical Ad. The video was a modified cartoon version of the band's actual music video.
The man at the employment agency plays a game clearly modelled after Doom.
The scene in which Mr. Burns revives Smithers is a parody of the Disney movies Snow White and the Seven Dwarves (the glass coffin) and Sleeping Beauty (Smithers being locked in a palace room and wake up by Burns‘s mouth).
The banner at the U.S.-Canadian border reads that Canada is now "Celine Dion Free", a reference to Canadian singer Celine Dion moving to Las Vegas to perform nightly at Caesars Palace.
The song that is playing when Homer and Grandpa are getting the drugs is "White Rabbit" by Jefferson Airplane, a song with thinly veiled drug references.
The Springfield Air and Space Museum is a parody of the National Air and Space Museum in Washington, D.C.
Burns and Smithers flying by the moon in a makeshift aircraft while Burns says "Next stop... Pirate Island!" is a parody of E.T. The Extraterrestrial.
There is a plane at the Springfield Air and Space Museum called "Spirit of Shelbyville", which is a reference to the Spirit of St. Louis, a plane used by Charles Lindbergh to fly solo across the Atlantic.
As they bicker in the back of the car Ned mentions Hawkman which may be a reference to the DC Comics superhero.
The song played when Doctor Hibbert is discussing the drug companies is "Baby Got Back" by Sir-Mix-A-Lot.
Pfizer is also a real life pharmaceutical research company based in New York.
When the Canadian Ned offers Flanders a "reeferino" and says that "it's legal here", this is somewhat incorrect as non-medicinal marijuana is still technically illegal in Canada, but punishment for possession of the drug in small amounts is relatively minor, and jail time for possession is very unlikely. This scene makes reference to the ongoing debate about the decriminalization of marijuana in Canada.
When Homer, Grandpa, Ned and Apu are returning to the United States, they encounter an RCMP officer at the border, in full uniform. In actuality, RCMP officers only wear the Red Serge on special occasions; as well, the CBSA is responsible for patrolling the border on the Canadian side, not the RCMP. Additionally, in reality when crossing the Canada - United States border, people only need to check in with the country they are entering, not the one they are leaving. These three exact errors also happened in an episode of That 70's Show. One more small issue is when one RCMP officer asks the other if Homer had a passport, when in reality passports at the time were not required to cross the border.
Earlier in the show Mr. Burns mentions that rain makes the Plywood Pelican catch fire. Later, it is shown in a dock.
Krusty the Clown mentions that he needs lithium dibromide (LiBr) to treat his bipolar disorder. There's no such chemical; the writers either mean lithium bromide (which is used in air-conditioning systems) or lithium carbonate (which is prescribed to people who have bipolar disorder). Lithium dibromide is also incorrectly named using the system of IUPAC nomenclature of inorganic chemistry. However, Krusty could have gotten the name wrong because of his illiteracy.
During their last drug run, when Homer asks Johnny Canuck how he can repay him, Johnny Canuck responded by saying that he would like to see someone "with an IQ of a child get executed by the state" because they "don't get that up here." Canada officially abolished the death penalty in 1976.
Despite being prohibited from returning to Canada in this episode, he return here with his family for the 2010 Winter Olympics in "Boy Meets Curl".
This episode contains many references to aerospace and its history.
The Plywood Pelican, which is an obvious reference to Howard Hughes' Spruce Goose, which in turn also references the Simpsons episode $pringfield in which Mr Burns has a similar plane named the Spruce Moose.