A single dose of psychedelics robustly yet transiently elevates neural activity, leads to a large-scale engagement of neural plasticity, and may provide immediate and enduring relief from treatment-resistant depression, end-of-life anxiety, or withdrawal symptoms in addiction. We focus on the multiple neuron types that mediate excitatory or inhibitory activity in the prefrontal cortex and address the lack of a high-resolution, genome-wide understanding of how psychedelics induce plasticity in distinct cell types at the transcriptomic level. In parallel, we measure how psychedelics induce long-lasting plasticity in select cell types in the prefrontal cortex at the physiological level. By explicitly addressing the relationship between intrinsic and synaptic plasticity, we assess how a large-scale plasticity event induced by psychedelics does not destabilize neural networks but instead induces cognitive flexibility.