A non-hallucinogenic psychedelic analogue with therapeutic potential.

Abstract

The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals.1 Unlike most substance use disorder (SUD) medications, anecdotal reports suggest that ibogaine possesses the potential to treat patients addicted to a variety of substances including opiates, alcohol, and psychostimulants. Like other psychedelic compounds, its therapeutic effects are long-lasting,2 which has been attributed to its ability to modify addiction-related neural circuitry through activation of neurotrophic factor signaling.3,4 However, several safety concerns have hindered the clinical development of ibogaine including its toxicity, hallucinogenic potential, and proclivity for inducing cardiac arrhythmias. Here, we apply the principles of function-oriented synthesis (FOS) to identify the key structural elements of its potential therapeutic pharmacophore, enabling us to engineer tabernanthalog (TBG)—a water soluble, non-hallucinogenic, non-toxic analog of ibogaine that can be prepared in a single step. TBG promoted structural neural plasticity, reduced alcohol- and heroin-seeking behavior, and produced antidepressant-like effects in rodents. This work demonstrates that through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant with therapeutic potential.