Several microstructural models have been proposed to increase the specificity of diffusion MRI. However, improper model assumptions can compromise the accuracy of model estimates. Here, we compared model-independent metrics extracted from double diffusion encoding (DDE) with the metrics arising from the current (two-compartment) diffusion “standard model” (SM) in in-vivo rat brains. Our results revealed that SM produces overestimated microscopic anisotropy for both white and grey matter. These findings question the validity of SM and calls for future developments of more accurate models.