Ibogaine, a psychedelic alkaloid, shows anti-addictive effects in humans and animals but has safety issues including toxicity and heart arrhythmias. Researchers engineered tabernanthalog, a water-soluble, non-hallucinogenic, non-toxic analogue made in a single step. In rodents, tabernanthalog promoted structural neural plasticity, reduced alcohol- and heroin-seeking behavior, and produced antidepressant-like effects. This demonstrates that careful chemical design can create safer, non-hallucinogenic variants of psychedelic compounds with therapeutic potential.
Cortical neuron atrophy, including neurite retraction and spine loss, is a hallmark of depression. Psychoplastogens are small molecules hypothesized to reverse these changes. Ketamine and LSD, from two structurally distinct chemical classes, promote sustained growth of cortical neurons after brief stimulation. This growth occurs in two phases: an initial stimulation phase requiring TrkB activation, followed by a growth period needing sustained mTOR and AMPA receptor activation. These temporal details suggest that rapidly excreted psychoplastogens could be effective neurotherapeutics with advantages over ketamine and LSD.
Thirteen psychoactive compounds from different chemical classes were screened in larval zebrafish for developmental toxicity. Psychedelic tryptamines and ketamine were less neurotoxic than LSD and psychostimulants. The results provide a reference database for comparing neurotoxicity profiles of novel psychedelics being developed as therapeutics.