Engineering non-hallucinogenic versions of psychedelics to treat psychiatric conditions

By David E. Olson, Associate Professor, Department of Chemistry and Department of Biochemistry & Molecular Medicine

August 1, 2022

Changes in neuronal structure are at the heart of neuropsychiatric conditions such as depression, substance use disorder, and post-traumatic stress disorder (PTSD), as well as developmental conditions such as schizophrenia and autism.  The development of safe medications that could reverse or repair these neuronal alterations is an active area of research.  In 2018, David E. Olson and his lab discovered that psychedelics, like LSD and MDMA, promote neuroplasticity and facilitate the growth of cortical neurons—a finding that could explain why psychedelics produce long-lasting therapeutic effects after a single dose.  Though psychedelics are demonstrating promising results for treating depression, PTSD, and social anxiety in adults with autism under carefully controlled and monitored conditions, the wider use of these treatments is limited by their hallucinogenic effects, potential for heart damage, and/or psychostimulant properties. 

To solve this issue, the Olson Lab has engineered several non-hallucinogenic versions of psychedelics that produce therapeutic effects in preclinical models with improved safety profiles. Their non-hallucinogenic version of the drug ibogaine, known as tabernanthalog (TBG) was described in a paper published in Nature last December. It  produces therapeutic effects in models of depression, opioid use disorder, and alcohol use disorder, though the compound has not yet been tested in humans.

More recently, the Olson Lab partnered with Lin Tian’s group to develop psychLight—the first ever optical test for determining the hallucinogenic potential of specific compounds . In a paper published in Cell, the team used psychLight to identify AAZ-A-154 (AAZ), a non-hallucinogenic MDMA-like compound with long-lasting antidepressant effects but no psychostimulant properties. Olson and his team are currently testing the effects of AAZ in experiments relevant to treating PTSD and social anxiety in adults with autism. Olson Lab research also led to the founding of Delix Therapeutics—a biotech company focused on using non-hallucinogenic analogs of psychedelics to treat a variety of neuropsychiatric and neurodegenerative conditions.

Psychiatric conditions (like depression, substance use disorder, and PTSD) and developmental conditions (like schizophrenia and autism) cause changes to the brain structure. Neurons are the cells that transmit messages in the brain. Neroplasticity is the brain’s ability to adapt to change by forming new connections. Psychedelic drugs like LSD and MDMA promote neuroplasticity and neuron growth. This could help treat conditions that change brain structure, but their use is limited because of their hallucinogenic properties & risk of heart damage. Researchers have engineered new, non- hallucinogenic versions of these drugs to get the therapeutic effects more safely. TBG Synthetic version of the drug ibogaine Therapeutic effect in models of depressions and substance use disorders. Not yet tested in humans. AAZ Drug similar to MDNA. Long-lasting antidepressant effects. No stimulant effects. Currently being tested to treat PTSD & social anxiety in autism.