How Do You Strip a Psychedelic of Its Hallucinogenic Properties? Chemical Evolution

While people have touted the therapeutic benefits of psychedelics for decades, it’s only been within the last five years that UC Davis researchers discovered that compounds like LSD, DMT and psilocybin promote neuroplasticity, spurring the growth and strengthening of neurons and their connections in the brain’s prefrontal cortex. This region of the brain experiences neural atrophy in illnesses like depression, post-traumatic stress disorder and substance use disorder, among others.   

Spearheading this research is David Olson, the founding director of the UC Davis Institute for Psychedelics and Neurotherapeutics (IPN). At the IPN, Olson and other researchers are dissecting psychedelic compounds to isolate their neurotherapeutic benefits, divorcing them from their hallucinogenic and potentially harmful properties.  

“There’s a whole bunch of patients that cannot receive psychedelics because of co-occurring conditions or a family history of psychotic illness,” said Olson, who holds joint appointments in the Department of Chemistry and the Department of Biochemistry and Molecular Medicine. “So we want to differentiate between their plasticity-promoting effects and their subjective effects, their effects on perception.”  

The research has led to the creation of a new class of small molecule drugs called non-hallucinogenic psychoplastogens. Chemically inspired by their psychedelic counterparts, these drugs are designed to harness the beneficial neuroplasticity-promoting effects, divorcing them from hallucinations and other potentially negative effects. 

But how do researchers strip a psychedelic of its hallucinogenic properties? 

Reverse engineering a psychedelic 

The age of psychoplastogens was ushered in by recent advances in neuroscience. Since the dawn of pharmaceuticals, chemists have synthesized drugs designed to treat various conditions and illnesses. But it’s only been recently that neuroscience tools have advanced enough to give researchers a window into how psychedelics affect the brain.   

“We’re reverse engineering things that we know have clinical efficacy,” Olson said. “So we’re taking drugs like ibogaine, psilocybin, LSD and MDMA and trying to figure out how they work, what their mechanisms are and tweaking their chemical structures to make them better versions of themselves.”  

Using nuclear magnetic resonance techniques, Olson and his colleagues can see what is otherwise invisible to the naked eye — the chemical structures of these compounds. They then conduct structure-activity relationship studies in which they tweak the compound’s molecular structure and observe how that affects their function.  

"You start with a molecule and then you make small modifications and over time, the structure changes, so it starts looking like something completely different than it did before,” Olson said. “It’s almost like chemical evolution.”  

Take ibogaine, for example. Derived from the iboga shrub, the drug has been used to treat substance use disorder and alcohol addiction.  

“There is some evidence at least anecdotally that people with opioid use disorder can take a single dose of ibogaine and be drug-free for up to six months and with the second dose, they can be drug-free for up to three years, which is remarkable,” said Olson.  

Despite these benefits, ibogaine isn’t a perfect drug. One adverse effect is that it binds to an ion channel in the heart that can cause cardiac arrhythmias leading to heart attacks.    

“For ibogaine, we were able to chop off a part of the molecule that was responsible for producing these cardiotoxicity effects,” he added. “We also shuffled around a few atoms to get rid of the hallucinogenic effects.”

The researchers isolated ibogaine’s beneficial neuroplasticity effects in an analog drug called tabernanthalog, the chemical structure of which hinged around the neuroplasticity-producing tetrahydroazepine ring. Tested on mice with binge-drinking behavior and heroin-seeking rats, the analog drug rapidly reduced alcohol consumption and heroin-seeking behavior, sustaining the effect for days after the drug was cleared from the body, according to research published in Nature.    

But how do researchers confirm a psychoplastogen doesn’t cause hallucinations? 

Olson and Lin Tian, an associate professor at the UC Davis School of Medicine, answered this very question by developing a genetically encoded sensor called psychLight. The biosensor, which is based on the serotonin 2A receptor, produces a specific fluorescent profile when activated by a molecular compound with hallucinogenic effects. 

A brighter future 

To bring novel psychoplastogens to market, Olson founded Delix Therapeutics, a company aiming to produce these pharmaceuticals at scale. Already, the company is making headway.  

In June 2023, Delix Therapeutics announced that it completed the first round of phase 1 clinical trials for a non-hallucinogenic psychoplastogen that takes inspiration from the chemical structures of MDMA and 5-MeO-DMT. Another compound currently in development is partially inspired by the chemical structure of ibogaine. 

“I’m very hopeful for a day when psychedelics will be FDA-approved treatments for various conditions and they will definitely help some patient populations. But to be administered safely, psychedelics have to be given under the supervision of health care professionals in a clinical setting, which drastically limits the scalability of these treatments,” Olson said. “If we can produce non-hallucinogenic psychoplastogens with similar efficacy, we will have medicines that can benefit many more patients.”  

Learn more about the UC Davis Institute for Psychedelics and Neurotherapeutics. 

— Greg Watry, content strategist & writer for the College of Letters and Science at UC Davis