A newly designed compound, (+)-JRT, structurally similar to LSD but with reduced hallucinogenic effects, promotes the growth of dendritic spines in the cortex—a process that is diminished in neuropsychiatric diseases such as depression, addiction, and schizophrenia. In behavioral tests, (+)-JRT showed antidepressant-like and cognition-enhancing effects without worsening signs related to psychosis. This suggests that nonhallucinogenic compounds that promote neuroplasticity could be safer alternatives to psychedelics for treating conditions where psychedelics pose risks.
Nonhallucinogenic psychoplastogens like tabernanthalog (TBG) promote cortical neuroplasticity through the same biochemical pathway as classic psychedelics—involving 5-HT2A, TrkB, mTOR, and AMPA receptor activation—but without inducing an immediate glutamate burst or immediate early gene activation. TBG-induced cortical spinogenesis is required for its sustained antidepressant-like behavioral effect in rodents. These findings clarify how certain psychoplastogens can produce neuroplasticity without hallucinogenic effects, challenging assumptions that glutamate burst and IEG activation are necessary for psychedelic-induced neuroplasticity.