Given the slow washout of CNO, it would be great if one could stop its effects on hM4Di with some drug (that ideally does not affect native M4 receptors). Bryan Roth mentioned in his 2016 Neuron Primer "DREADDs for Neuroscientists" that
"creation of DREADD antagonists would also be potentially highly useful", so apparently at that time there still was none. I would think it might be possible to create/discover something that eg blocks the CNO binding site, but so far found nothing!
I only found a paper from 2008 that looked into this a bit but did not find any antagonists (https://www.ncbi.nlm.nih.gov/pubmed/18628403). If anyone knows of anything, would be great to hear about it!