Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are an increasingly popular approach for “remotely controlling” selected neuronal populations and pathways (Armbruster et al, 2007). Gomez et al, 2017 provides important new details on an underappreciated mechanism by which DREADDs can produce CNS effects following peripheral administration of clozapine-n-oxide (CNO). A small proportion of systemically-administered CNO is metabolized to clozapine (Jann et al, 1994; MacLaren et al, 2016), an antipsychotic drug with activity at numerous endogenous receptors (Ashby and Wang 1996; Selent et al, 2008), and they show, as previously reported, that clozapine both much more readily penetrates the blood brain barrier (BBB)(Cremers et al, 2012; Hellman et al, 2016) and more potently binds DREADDs than CNO (Armbruster et al, 2007). They conclude that clozapine is therefore likely to be a major contributing factor activating DREADDs after systemic administration of CNO. This report has given pause to hundreds of labs using DREADDs to control neural circuits in vivo. If present at high enough concentrations to affect endogenous receptors, clozapine could cause effects beyond those mediated by CNO acting at DREADDs. We agree with the authors that these findings do not discount conclusions drawn from wellcontrolled DREADD experiments, but they highlight several important issues regarding interpretation of data from DREADD experiments and choice of DREADD agonist for use with designer receptors going forth. First, this study shows that clozapine back-metabolized from CNO may contribute to DREADD activation after peripheral CNO injection. Gomez et al report that clozapine metabolized from CNO accumulates over time (although see (MacLaren et al, 2016)), such that effects of clozapine may be strongest long after CNO injection (> 2 h). Therefore, it is important to consider whether clozapine accumulates after CNO injection to concentrations sufficient to activate endogenous receptors classically associated with clozapine (eg, 5-HT, dopamine, or histamine receptors). In addition, unwanted effects of back-metabolized clozapine may also depend on the behavior in question and the presence or absence of other pharmacological agents (eg, selfadministered cocaine) that could interact with clozapine’s endogenous (non-DREADD) receptor targets (Bun et al, 1999; MacLaren et al, 2016; Gomez et al, 2017). It is also possible that low doses of clozapine could cause complex effects via concurrent actions at DREADDs and at endogenous receptors present in the same neurons or circuits. This means that even if the CNO/clozapine concentration is low enough to cause no observable effects in non-DREADD-expressing animals, its actions at endogenous receptors could interact with DREADD effects in unknown ways. Therefore, knowledge of clozapine blood and brain levels over time after CNO application is important, and caution is warranted for studies examining prolonged testing periods, repeated CNO administrations, and especially chronic CNO dosing. In general, effects of any DREADD agonist should be compared in DREADD-expressing versus non-DREADD-expressing animals, allowing identification of DREADD-specific effects. The potential for long-lasting effects of DREADD agonists on outcomes occurring outside the~ 2 h testing window after acute dosing should also be examined. The authors suggest that the best path forward for DREADD users is to switch to low-dose clozapine instead of CNO, thus removing potential variability in CNO metabolism and therefore clozapine dosing; however, there …