During adolescence, cannabis experimentation is common, and its association with inter-individual variations in brain maturation well studied. Cellular and molecular underpinnings of these system-level relationships are, however, unclear. We thus conducted a three-step study. First, we exposed adolescent male mice to Δ-9-tetrahydrocannabinol (THC) or a synthetic cannabinoid WIN 55,212-2 (WIN) and assessed differentially expressed genes (DEGs), spine numbers and dendritic complexity in their frontal cortex. Second, in human (male) adolescents, we examined group differences in cortical thickness in 34 brain regions, using magnetic resonance imaging, between those who experimented with cannabis before age 16 (n=140) and those who did not (n=327). Finally, we correlated spatially these group differences with gene expression of human homologs of the mouse-identified DEGs. The spatial expression of 13 THC-related human homologs of DEGs correlated with cannabis-related variations in cortical thickness, and virtual histology revealed co-expression patterns of these 13 genes with cell-specific markers of astrocytes, microglia and a type of pyramidal cells enriched in dendrite-regulating genes. Similarly, the spatial expression of 18 WIN-related human homologs of DEGs correlated with group differences in cortical thickness, and showed co-expression patterns with the same three cell types. Gene ontology analysis indicated that 37 THC-related human homologs are enriched in neuron-projection development, while 33 WIN-related homologs are enriched in processes associated with learning and memory. In mice, we observed spine loss and lower dendritic complexity in pyramidal cells of THC-exposed animals (vs. controls). Experimentation with cannabis during adolescence may influence cortical thickness by impacting glutamatergic synapses and dendritic arborization.Significance Statement Cells and molecular underpinning of cannabis-related variations in cortical thickness observed in adolescents are poorly understood. We assessed differences in gene expression in the frontal cortex of adolescent mice exposed (or not) to Δ-9-tetra-hydrocannabinol (THC) or WIN 55,212-2 (WIN). THC preferentially targeted glial cells, while WIN affected pyramidal neurons; both modified nuclear-coded subunits in mitochondrial respiratory complexes and excitatory synapse genes. In humans, we evaluated a spatial correlation between group differences in cortical thickness and the expression of human homologs of the cannabinoid-sensitive genes in mice. These genes co-expressed with those specific to astrocytes, microglia and a type of pyramidal cells enriched in dendrite-regulating genes. Experimentation with cannabis during adolescence may influence cortical thickness via synaptic processes and dendritic arborization.