Serotonergic psychedelics are emerging as alternative therapies for treatment-resistant depression; however, their hallucinogenic effects may limit their widespread clinical use. Second-generation psychedelics, which lack hallucinogenic effects, are a promising alternative. 2-Bromo-LSD (2-Br-LSD/BETR-001) is an LSD derivative with 5-HT2A partial agonist activity that lacks hallucinogenic effects. Thus, 2-Br-LSD may represent a possible novel therapeutic for treating neuropsychiatric diseases. We assessed the effects of 2-Br-LSD on stress-coping behaviour in mice, using the forced swim test, and exploratory behaviour in the open field test. This was followed by spine analysis in the prefrontal cortex using Golgi-Cox staining to evaluate neuroplastic correlates. We found that 2-Br-LSD treatment induces cortical plasticity and promotes active stress-coping behaviours. Then, we performed bulk RNA sequencing from the prefrontal cortex to identify genes underlying the stress-coping and neuroplastic effects of 2-Br-LSD. Transcriptomic analysis revealed several enriched GO/KEGG pathways related to neuroplasticity and neurotransmission and many gene targets involved in dopaminergic signaling, axon guidance and addiction. Not only do our results show that 2-Br-LSD represents a promising alternative to classic psychedelics in treating depression, but the sequencing results indicate further therapeutic potential beyond mood disorders.