Post-traumatic stress disorder (PTSD) is associated with cognitive deficits, oxidative stress and inflammation. N,N-dimethyltryptamine (DMT) is a known neuroprotective, antioxidant, anti-inflammatory, and psychoplastogen with antidepressant effects. Therefore, we tested the capacity of DMT, the monoamine oxidase inhibitor (MAOI) harmaline, and “pharmahuasca” (DMT + harmaline) to reduce reactive oxygen species (ROS) production and inflammatory gene expression and modulate neuroplasticity-related gene expression in a predator exposure and psychosocial stress rat model of PTSD. We administered DMT (2 mg/kg IP), harmaline (1.5 mg/kg IP), or pharmahuasca every other day for 5 days. We measured ROS production in the prefrontal cortex (PFC) and hippocampus (HC) by electron paramagnetic resonance spectroscopy (EPR) and extracted total RNA from the PFC for sequencing. We also performed in vitro assays to measure the affinity and efficacy of DMT and harmaline at the 5HT2AR. DMT and pharmahuasca reduced ROS production in the PFC and HC, while harmaline had mixed effects. RNA sequencing implicated genes related to ROS production, inflammation, neurotransmission, and neuroplasticity. DMT, but not harmaline exhibits both affinity and efficacy at the human 5HT2AR. DMT and pharmahuasca exhibit broad effects that may facilitate the treatment of PTSD by reducing ROS production and inflammatory gene expression, and inducing neuroplasticity.