There’s a running debate in psychedelic science about whether the psychedelic effects matter.
On one side, you have researchers who argue the mystical experience is the medicine – that ego dissolution and the sense of oceanic connection is what drives the therapeutic outcomes. On the other side, you have a growing contingent who believe that’s a romantic story we tell ourselves, and that the actual healing happens at the receptor level regardless of what the patient consciously experiences.
It’s a debate that’s been almost impossible to settle, because separating the pharmacology from the phenomenology has proven very difficult. Psychedelic compounds bind to the 5-HT2A serotonin receptor. That same receptor binding is what produces the perception-altering effects. Disentangle those two effects, and you have your answer.
A team at UC Davis may have just found a way to do that disentangling by building an entirely new compound using light.
Shining UV Light on Amino Acids
The approach the Mascal Lab used is unusual in drug discovery. Rather than taking a known psychedelic scaffold and making modifications to tune its pharmacology, the researchers started from amino acids, the building blocks of proteins, and combined them with tryptamine (a naturally occurring metabolite derived from tryptophan, the same amino acid you find in turkey and eggs, and the same one your body uses to produce serotonin).
They then shone ultraviolet light on the resulting molecules, which triggered a cascade of chemical changes, producing entirely new compounds that hadn’t existed before. Using computational modelling, the team screened 100 of these compounds against the brain’s 5-HT2A receptor (the primary target of classical psychedelics) and identified five worth studying in more detail.
Their activity levels ranged from 61% to 93%. The strongest compound, which the researchers named D5, was a full agonist. That means it triggered the maximum biological response the 5-HT2A system is capable of producing.
At which point, the scientists expected the mice to start twitching.
The Head Twitch Didn’t Happen
The head twitch response is the standard rodent proxy for hallucinogenic-like effects. When a compound activates 5-HT2A receptors in mice, the animals display a rapid, involuntary head rotation. It’s not a perfect readout, but it’s one of the most reliable behavioural indicators in the field, and it’s highly consistent across classical psychedelics: give a mouse psilocin, LSD, or DMT, and it twitches.
But D5 did not produce the twitch.. The researchers describe how they expected hallucination-like behaviour, but they got the opposite.
The Mechanism
The leading hypothesis for why some 5-HT2A agonists produce hallucinations and others don’t comes down to a concept called biased agonism.
When a drug binds to a receptor, it doesn’t just turn the receptor on or off. Different drugs can activate the same receptor through different intracellular signalling pathways. Some pathways appear more associated with hallucinations (the Gq/IP pathway). Others are more associated with neuroplasticity, BDNF expression, and the kind of cellular changes that underlie therapeutic outcomes (the beta-arrestin pathway).
If D5 is activating the plasticity-linked pathways while leaving the hallucinogenic ones relatively untouched, that would explain the behavioural data in mice. The team doesn’t yet know if that’s what’s happening. Their next steps involve investigating whether other serotonin receptors might also be modulating or suppressing D5’s hallucinogenic potential.
What they do know is that D5 activates serotonin signalling pathways linked to brain plasticity. The hallucination question, as co-author Trey Brasher put it, is now the thing worth understanding: “Why D5 and similar molecules are non-hallucinogenic when they’re full agonists.”
Why This Is More Interesting Than “Psychedelics Without the Trip”
The popular framing of this research will predictably be: psychedelics without the scary part. A safe version for people who can’t or won’t take on a full psychedelic experience. That framing isn’t wrong exactly, but it undersells what’s actually happening here.
What UC Davis have demonstrated is that the chemical space around 5-HT2A pharmacology is far larger and more varied than anyone assumed. For decades, the dominant approach in psychedelic medicinal chemistry has been modification – take a known scaffold, change a functional group, see what shifts. Ph.D. student Joseph Beckett describes this as “tweak the pharmacology a little bit one way or another.” BUt D5 and its relatives are an entirely new class of compounds.
If UV-driven photochemistry can generate novel serotonin receptor ligands from amino acid precursors, the diversity of compounds worth investigating just expanded dramatically. Some of those compounds will be hallucinogenic. Some, apparently, won’t be. Some may hit entirely different receptor subtypes. The scaffold itself, the researchers note, possesses a range of activity that’s not yet mapped.
The question of whether the trip is necessary for the therapy also comes into focus. If D5 produces neuroplasticity-related receptor activation without the altered state, and if a future clinical trial shows therapeutic outcomes, that would be strong evidence that the phenomenology is downstream of the pharmacology, not the cause of it.
If it doesn’t produce therapeutic outcomes, that’s equally important data.
Final Thoughts
This is a preclinical study in mice. The gap between rodent models and human therapeutic application in psychedelic research has proven wide and humbling. D5 has activated a receptor. It hasn’t treated depression. It hasn’t been tested in a single human. The path from here to a clinical application is long, involves substantial safety profiling, and may reveal that D5’s properties in mice don’t translate the way researchers hope.
What this study has done is open up a possibility. Finding a brand-new scaffold that hits 5-HT2A with full agonist activity and doesn’t trigger psychedelic-like behaviour in rodents is novel.
The field now needs to understand why.
Source: Transforming Amino Acids into Serotonin 5-HT2A Receptor Ligands Using Photochemistry. Journal of the American Chemical Society, 2025; 147 (52): 48400 DOI: 10.1021/jacs.5c19817
The Spore Report covers the emerging science of fungi, psychedelics, and brain health. If this kind of work interests you, subscribe here.
