Non-hallucinogenic Psychoplastogens: Decoupling Neuroplasticity from Hallucinations for Cancer-Related Cognitive Impairment and Aging Brain Repair

Classical psychedelics such as psilocybin and LSD induce rapid and sustained neuroplasticity via 5-HT2A receptor activation and downstream TrkB–mTOR–AMPA signaling, resulting in durable improvements in depression, anxiety, and existential distress. Randomized controlled trials in cancer patients have demonstrated long-lasting reductions in anxiety and depression; however, hallucinogenic effects substantially limit clinical applicability, particularly in populations vulnerable to psychosis. Recent advances in non-hallucinogenic psychedelic analogs (psychoplastogens) overcome this limitation by dissociating neuroplasticity from perceptual alteration. Compounds such as tabernanthalog (TBG) and JRT, a structurally modified LSD analog, retain robust plasticity-promoting effects while largely eliminating hallucinogenic activity. These agents enable the therapeutic exploitation of psychedelic-like plasticity in conditions previously considered contraindicated, including cancer-related cognitive impairment (CRCI), schizophrenia negative symptoms, and age-related cognitive decline. This paper integrates emerging evidence on non-hallucinogenic psychoplastogens and proposes a time-segregated mTOR strategy to reconcile oncologic mTOR inhibition with post-treatment brain repair. Precision control of neuroplasticity is positioned as a foundational paradigm for next-generation neuro-oncology and aging medicine.