The recent discovery that the psychedelic drug N,N-dimethyltryptamine (DMT) can be found in the brain with concentrations comparable to classic monoamine neurotransmitters has raised the question regarding the role of endogenous DMT. DMT is known to have high affinity for the 5-HT2A receptor (2AR) and can induce changes in neural plasticity through a 2AR dependent manner, the mechanism believed to underly the rapid acting-antidepressant effects. However, not all 2AR ligands have this effect. Serotonin, the endogenous 2AR ligand, does not produce changes in neural plasticity in our assays. We hypothesize this is due to the largely intracellular localization of the 2AR in neurons. Using cultured cortical neurons, which heavily express the 2AR, our results demonstrate that stimulation of the intracellular pool of 2ARs in neurons is necessary for the induction of neural plasticity. They also suggest N-methyltryptamines like DMT may play a role in regulating neural plasticity within the cortex through stimulation of intracellular 2ARs.