Psychedelics and Non-hallucinogenic Analogs Use the Same Serotonin 2A Receptor Pathway, But Differ in Gene Activation

5-MeO-DMT and the non-hallucinogenic psychedelic analog tabernanthalog (TBG) both promote neuroplasticity through the same serotonin 2A (5-HT2A) receptor pathway, but “up to a point” they diverge in how strongly they activate downstream biology. Rodent studies using pharmacological and genetic tools found that both compounds activate similar downstream signaling, including TrkB, mTOR, and AMPA, and that TBG acts as a partial agonist while 5-MeO-DMT is a full agonist. Researchers report that TBG increases dendritic spine growth in the prefrontal cortex and can produce sustained antidepressant-like effects. Experiments using advanced genetic tools to erase the newly grown dendritic spines showed that the antidepressant-like benefit depends on those neuroplastic changes. The study also challenges a prevailing model by showing that TBG promotes plasticity without the glutamate burst and immediate early gene activation associated with hallucinogenic effects, suggesting those processes may be tied more to hallucinations than to therapeutic neuroplasticity.