"There are rumours that part of the problem was that Brad was allegedly drinking and smoking too much weed. I wonder why he would need to self-medicate?" Handler asked on her Netflix talk show on Tuesday.

"Maybe because he could have been spending the last 12 years at Lake Como hanging out with George Clooney and Matt Damon instead of being stuck in a house with 85 kids speaking 15 different languages.

"Oh yeah, because he married a f---ing lunatic, that's why."

The host has been firm friends with the former Friends star, best known for playing American sweetheart Rachel Green, for years, with Handler attending Aniston's intimate wedding to second husband Justin Theroux in August last year.

Aniston has mostly taken the high road on all things Jolie-Pitt, keeping a dignified silence on the relationship that first began in murky waters on the set of their now iconic spy thriller Mr. & Mrs. Smith in 2004, while Pitt was still married to Aniston.

Their split was the perfect opportunity for an outspoken Handler to show she was firmly on "Team Aniston" by mocking the Hollywood power couple, and possibly giving a some insight into previous discussions she has had with Aniston on the pair.

Tabloids have used Aniston as fodder for more than a decade, painting her as the spurned victim and Jolie the vixen after Pitt "fell in love" with the Lara Croft star.

Since the divorce was announced, the tabloids have been having a field day with The New York Post putting a laughing Aniston on the front cover, while Us Weekly's report on Aniston saying "that's karma for you" when she heard about the Jolie-Pitt demise should possibly be taken with the largest grain of salt.

Meanwhile, Handler's mentioning Pitt's good friend Clooney might have been in vain, since he first heard about their break up during an awkward interview with CNN.

"I didn't know that," a stammering Clooney replied when he was told the news. "That's... wow. I feel very sorry [for them], then.

Jolie filed for divorce in Los Angeles Superior Court on Monday, citing irreconcilable differences, court documents showed.

She has sought physical custody of their six children, Maddox, 15, Pax, 12, Zahara, 11, Shiloh, 10, and twins Knox and Vivienne, eight.