The evolution of the psychedelic revolution

Atrophy of pyramidal neurons in the prefrontal cortex (PFC) is a hallmark of stress-related neuropsychiatric diseases such as depression, post-traumatic stress disorder (PTSD), and addiction. Given the critical role of the PFC in top-down control of mood, fear, and reward, strategies aiming to restore PFC structure and function have the potential to be disease-modifying and broadly efficacious. Psychoplastogens are a class of compounds that can rapidly rectify pathological changes in PFC circuitry after a single administration, with ketamine and serotonergic psychedelics being prime examples [1]. The rapid and sustained therapeutic effects of psychoplastogens clearly differentiate them from traditional antidepressants.

While their therapeutic properties are exciting, first-generation psychoplastogens like ketamine, psilocin, and 3,4-methylenedioxymethamphetamine (MDMA) suffer from safety issues such as abuse potential, cardiotoxicity, and/or psychostimulant properties. Moreover, the hallucinogenic/dissociative effects of first-generation psychoplastogens drastically limit the scalability of these treatments by necessitating in-clinic administration. While the role of mystical-type experiences in the therapeutic properties of first-generation psychoplastogens is the subject of intense debate, mounting evidence suggests that beneficial psychoplastogenic effects can be achieved without inducing hallucinations [2].

Through rational chemical design, our group engineered the first analogs of psychedelics that increase cortical neuron growth at nanomolar concentrations, yet do not induce behavioral effects characteristic of hallucinogens [3]. Shortly after this initial report, we disclosed the development of tabernanthalog (TBG), a structural analog of 5-MeO-DMT and ibogaine with an improved safety profile including lower cardiotoxicity and reduced hallucinogenic potential [4]. Despite not eliciting a head-twitch response—a behavior characteristic of serotonergic hallucinogens—TBG produces effects on neuronal structure comparable to psychedelics. In cortical neuron cultures, TBG increases both dendrito- and spinogenesis, and two-photon imaging studies revealed that TBG promotes spine growth in vivo to a similar extent as the hallucinogenic drug 2,5-dimethoxy-4-iodoamphetamine (DOI) [4].

Like psychedelic compounds, TBG appears to have broad therapeutic potential, presumably due to its ability to impact the structure/function of pyramidal neurons in the PFC. A single administration of TBG produces a rapid antidepressant response as well as antiaddictive effects in alcohol and heroin self-administration assays that last long after TBG has been cleared from the body. Most impressively, a single dose of TBG rescues stress-induced deficits in dendritic spine density, cortical neuron calcium dynamics, parvalbumin-positive interneuron function, and behavioral effects related to anxiety, sensory processing, and cognitive flexibility [5].

To facilitate drug discovery efforts aimed at identifying safer analogs of psychedelics like TBG, we recently engineered psychLight, a biosensor based on the 5-HT2A receptor capable of predicting hallucinogenic potential [6]. Using psychLight, we identified AAZ as a new psychoplastogen that, like TBG, produces sustained therapeutic effects after a single administration and has low hallucinogenic potential [6]. Using psychoplastogens to rewire pathological neural circuitry represents a paradigm shift in neuropsychiatry, though first-generation compounds like ketamine and psychedelics will inevitably be limited in scope. Ultimately, we need to identify medicines capable of producing long-lasting beneficial changes in neural circuits without abuse potential and cardiotoxicity if we hope to develop scalable solutions for the large number of people impacted by neuropsychiatric diseases.

Author contributions

The authors both contributed to the writing and editing of this manuscript.

Funding and disclosure

This work was supported by funds from the National Institutes of Health (R01GM128997 to DEO, T32MH112507 to LPC) and Delix Therapeutics. David E Olson is a co-founder of Delix Therapeutics, Inc, serves as the chief innovation officer, is a member of the board of directors, and receives consulting fees. Delix Therapeutics has licensed technology from the University of California, Davis related to this manuscript. Lindsay P Cameron has nothing to disclose.