The "Pretty in Pink" star insists Sheen became a different guy as his marriage to the actress crumbled in 2006, and he hated to be around him.
"At first he could handle it, and he was still incredibly professional, and still lovely, by the way, to everybody on set - but you could just see that stuff was wearing on him," Cryer said told PeopleTV's Couch Surfing host Lola Ogunnaike.
In 2011, he was let go from the series for "dangerously self-destructive conduct," after a series of drug-related incidents and conflicts with the show's creator Chuck Lorre.
"It was one of the first internet s**tstorms, plus there's the fact that all of our jobs are tied into this guy, and we're all his friends," Cryer added. "It was very, very strange and (there were) aspects of it that I absolutely hated, but you know, I'm thankful for the years that were great," he added.
Sheen was replaced on the hit comedy by Ashton Kutcher.