A new study in mice suggests psychedelics make the brain more likely to “see” images from memory rather than what’s actually in front of it.
Long before modern laboratory testing, indigenous cultures used these substances to
treat psychological and physical ailments. The Aztecs used psilocybin mushrooms as medicine, while Andean cults consumed mescaline-rich San Pedro cacti thousands of years ago. Archaeologists have found a ritual bundle thousands of years old in a Bolivian cave that contains traces of DMT (a potent hallucinogenic found in plants). They also found 5,000-year-old peyote buttons from Texas.
The modern journey began when Swiss chemist Albert Hofmann synthesised LSD in 1938.
In the 1970s and 80s, researchers found that these drugs attach to a specific brain receptor (called 5-HT2A) that can trigger hallucinations. This receptor is part of the serotonin system, which affects mood and can influence anxiety and depression.
Fast-forwarding to today, scientists debate whether the psychedelic trip itself (the mystical experience) is necessary for treating conditions like depression and anxiety. Some scientists think the real benefit of psychedelics comes from their ability to help brain cells rewire and communicate in new ways – a process called “neuroplasticity”. It’s possible the hallucinations are just a side-effect of their therapeutic effect.
It is therefore critical to understand exactly how these substances alter people’s perception. Trends in modern pharmacology are shifting towards drug designs that aim to trigger the therapeutic “trip” of hallucinogens without the side-effects.
In the new study, scientists used mice engineered so certain brain cells would glow when active. The brighter the glow, the more active the cells were.
Technologies developed by one of the study’s lead researchers, Thomas Knöpfel, allowed the researchers to record both increases and decreases in voltage across the surface of the brain. These changes in voltage depend on which cells are being activated for specific tasks.
During the experiment, the mice were shown visual stimuli, such as moving black and white bar patterns, as well as simple blank screens. This allowed the researchers to measure brain activity during both stimulus viewing and resting states.
Halfway through the experiment, the researchers injected the mice with a powerful chemical that activates the same 5-HT2A serotonin receptor as LSD and psilocybin, but in a more selective and controlled way.
Psychedelic drugs can give people intense visual effects.
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The researchers compared the brain’s voltage patterns before and after the drug took effect, which helped them pinpoint the neural circuits affected by the psychedelic. They focused on the brain’s primary visual cortex and on slow rhythmic oscillations (known as theta rhythm) linked to attention, memory consolidation and stimulus familiarity. The high-resolution recordings revealed a fascinating shift in brain communication.
Before the drug, the visual cortex produced 5-Hz brain oscillations. After the psychedelic was administered, theta rhythm oscillations intensified significantly, increasing in both power and duration.
More importantly, these low frequency waves in the brain’s visual processing areas synchronised with the retrosplenial cortex, which has been implicated in the encoding, storing and retrieving memories. This synchronisation had a delay of about 18 milliseconds, consistent with a travelling wave of activity connecting the two regions.
The psychedelic acted like a switch: it dampened the brain’s response to what the eyes were seeing, while boosting connections with memory areas, letting the brain “fill in” missing visuals from its own memory.
Instead of relying on what was actually in front of the eyes, the brain began inserting fragments from its own internal memory banks. This finding provides an explanation for how visual hallucinations may work.
The lead researcher, Dirk Jancke, described this state as being remarkably similar to partial dreaming. Under the influence of the drug, the brain’s internal imagery overrides external reality, creating a vivid, self-generated world.
Despite these insights, the study has limitations. As acknowledged by the authors, some of the findings might reflect the mice getting distracted from the repetitive images. Mice and humans share several fundamental features of brain organisation, but it is unclear whether the phenomena can be mapped onto human hallucinogenic experiences.
Ultimately, though, the study could mark a crucial step towards developing non-hallucinogenic drugs that increase the patient’s neuroplasticity, and hopefully, decrease their mental health symptoms.