Cracking the chemical code

Scientists work to develop analogs of psychedelics without the trippy side-effects

Test tubes closeup on blue background.

When a plant has a medicinal property, chemists rush to create derivatives and analogs of it. It’s a pattern in Western medicine: Opium poppies became morphine. Coca leaves became lidocaine. Willow bark became aspirin. And, eventually, branded versions of each of those pharmaceutically developed drugs hit the market — making fortunes for the companies behind them and helping countless people manage with ailments. 

That process is accelerated when an illicit plant with known medicinal qualities becomes legal or decriminalized. We’re watching it happen in real time with natural psychedelics as places like Colorado end prohibition of them. These substances have real potential to help people therapeutically and science is starting to back that up. Three out of five Americans believe psychedelics should be legalized for therapeutic purposes, according to a recent study from UC Berkeley’s Center for the Science of Psychedelics (BCSP). 

So, naturally, the race is on to crack the chemical codes of psychedelic molecules. Researchers across the country are already trying to develop analogs that can be branded, distributed and sold commercially. And most of them are trying to develop versions that aren’t psychedelic at all. 

In May, the biopharmaceutical company Psilera announced the first drug in its extensive pipeline of chemical patents aimed at “reimagining” psychoactive natural products to create “effective and insurance-backed take-home therapies.” The drug, PSIL-006, is a chemically engineered molecule similar to psilocybin, the active ingredient in magic mushrooms. According to a Psilera press release, PSIL-006 showed efficacy in treating addiction, depression and end-of-life anxiety similarly to psilocybin — but without hallucinogenic effects. 

Similarly, researchers from UC Davis took a swing at creating their own analog of ibogaine. The psychedelic, derived from the African shrub Tabernanthe iboga, has shown incredible potential as an addiction treatment (Weed Between the Lines, “The addiction therapy drug,” April 6, 2023). 

In December 2020, those scientists published a paper in Nature, describing how they determined exactly what parts of the brain ibogaine affected and how, and engineered their own version of it: Tabernathalog. In rodent tests, the compound promoted neural plasticity in the brain, reduced alcohol- and heroin-seeking behavior, and produced antidepressant-like effects on mice. Similarly to Psilera’s PSIL-006, it did so without hallucinatory effects. 

A March 2023 paper in Cell Reports detailed another group of hopeful scientists who had developed a non-hallucinatory version of LSD. They called it 2-Br-LSD, and claim it similarly increased neuroplasticity, produced active coping behavior, and even reversed “chronic stress deficits.”

Those researchers concluded that 2-Br-LSD “may have profound therapeutic value for mood disorders and other indications.”

There are many groups of researchers currently working to develop non-hallucinatory psychedelic compounds for pharmaceutical use. Some, like DLX-1, aren’t even an analog of a known hallucinatory compound, but a molecule chemically engineered to light up the same receptor in the human brain that psychedelics affect. During in vivo studies, DLX-1 produced a similarly robust, long-lasting antidepressant effect on mice after just a single dose.

David Olson helped develop DLX-1. He is the co-founder and chief scientific officer of Delix Therapeutics. And while he doesn’t shy away from the financial prospects of developing such a molecule, he points out that having non-hallucinatory analogs of psychedelic compounds could be the best way of getting these drugs into the hands of people who need them most. 

In an interview with Technology Networks, Olson explains the cost of traditional psychedelic therapy might be out of reach for many people. There are also some with co-morbidities or family histories of psychotic illnesses who won’t be able to take them. And then there are those who simply don’t want to experience the hallucinatory effects of psychedelics but who could still benefit from using them. 

“What we really need are scalable solutions,” Olson said. “New first-line treatments that people can take home and put in their medicine cabinets. The only way we can get there is with non-hallucinogenic compounds that lack abuse liability.”