</ref> Several studies have shown that stimulants do not exacerbate tics any more than placebo does, and suggest that stimulants may even reduce tic severity. A 2011 Cochrane Collaboration review concluded that most major ADHD medications were effective in children with tics, and that stimulants did not generally worsen tics outside of individual cases. Methylphenidate, guanfacine, clonidine, and desipramine were associated with improvement of tic symptoms. Controversy remains, and the PDR continues to carry a warning that stimulants should not be used in the presence of tic disorders, so physicians may be reluctant to use them. Others are comfortable using them and even advocate for a stimulant trial when ADHD co-occurs with tics, because the symptoms of ADHD can be more impairing than tics.