Whereas Callén et al. (2012) showed a negative cross-talk in a heterologous expression system, the allosteric interaction in the CB1–CB2 heteroreceptor complex is synergistic in primary cultures of activated microglia activated with LPS and interferon gamma and in primary cultures of microglia from a transgenic model of Alzheimer’s disease (Navarro et al., 2018a). This evidence concerns the gene CNR1 and early-onset autosomal dominant Alzheimer disease.