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New Rat Study May Explain How LSD Triggers Hallucinations

By Alexander Beadle

Published: Nov 10, 2021   
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A breakdown of normal communication between the brain’s hippocampus and visual cortex may explain the hallucinations and altered behavior experienced while under the influence of LSD, a new study from Baylor College of Medicine suggests.

The research, published in the journal Cell Reports, compared the behaviors and brain activity of normal laboratory rats while they ran laps on a familiar running track. Under the influence of LSD, the rats ran less and displayed less neuronal activity in their hippocampi.

The researchers believe that this abnormal communication between the hippocampus and the visual cortex disrupted the internal mental “map” of the animals’ surroundings, effectively decoupling the animal’s internal perceptions from the real external environment. This abnormal communication could help to explain the hallucinations, dissociation, and other altered perceptions triggered by LSD use in humans, the researchers say.

Rats run less and twitch more under the influence of LSD

In this study, lab rats were trained to run laps back-and-forth on a c-shaped running track. The rats were given a saline injection and allowed to freely run around the track for 20-30 minutes while their behavior was recorded. After a three-hour resting period, the rats were injected with either a high or low dose of LSD or an inert control, and their behavior was measured again.

The researchers found that rats injected with LSD ran significantly fewer laps in the second running session than the rats in the control group. The median running speed of the rats who received LSD was also significantly lower, as was the median percent of time spent completely immobile.

Another key difference was the incidence of head-twitching events, where rats briefly and rapidly shake their head back-and-forth. Head-twitching in rodents and hallucinations in humans are both thought to be caused by psychedelics activating the 5-hydroxytryptamine-2-A receptor (5HT2AR), so head-twitching in rodents can be thought of as a behavioral signature of hallucinations. As expected, head-twitch rarely occurred in the first running session or in the control group, but was frequently seen in the rats given LSD before the second running session.

“Our lab is interested in improving the understanding of how the brain generates behavior,” study author Dr Daoyun Ji, professor of neuroscience at Baylor College of Medicine, said in a statement. “LSD triggers abnormal perceptions of the real world and altered behaviors. By studying how the drug works, we hope to gain insights into the neural mechanisms that mediate behavior.”

In addition to looking at the visual differences in behavior between the rats given LSD and the control group, the researchers also examined the real-time electrical spiking patterns of brain cells in the hippocampus, which is central to learning and memory, and the visual cortex.

​​“This would give us a measure of what was going on in the brain,” Ji explained.

LSD changes the activity of the hippocampus and visual cortex neurons

The scientists found that the overall spiking activity of neurons in both the hippocampus and visual cortex was reduced dramatically during movement in the rats given LSD.

“That means that when the animal was moving around in the track, the neurons generated fewer pulses, which probably affected the clarity of their guiding brain ‘map,’” Ji explained.

When an animal moves around new surroundings, the visual information created by looking around is sent to the visual cortex, which works with the hippocampus to remember this information and create an internal map of the area. By referencing this mental map, an animal can familiarize itself with its environment and navigate it more confidently in the future.

LSD appeared to change the spiking patterns in the hippocampus and visual cortex that are responsible for sustaining this map and giving the animal a sense of direction. Communication between the hippocampus and visual cortex was also reduced. The researchers believe that this decoupling between the rats’ internal map and the real world may explain why the rats under the influence of LSD moved more slowly and completed fewer laps of the running circuit. “We propose that LSD makes the map fuzzy,” Ji said.

The researchers also observed strange high-amplitude wave-and-spike events taking place in the visual cortex while the rats given LSD were immobile. Interestingly, these firing patterns are normally seen during the transition from wakefulness to sleep. However, because of the rapid onset of these events and the non-occurrence of any slow-wave sleep activity in the brain, the researchers say that the rats were not simply falling asleep on the track.

“These periods of inactivity triggered by LSD are like the normal transition from being awake to going to sleep,” Ji said. “It suggests that maybe the drug induces a state similar to a half-conscious state in which a lot of dreaming-like activity is happening. More research is needed to enlighten this finding.”

LSD and the brain

Researchers have been interested in LSD ever since it was first synthesized in the 1930s, though federal crackdowns on psychedelic drugs effectively ended the psychedelics research movement shortly after it began. But psychedelics research is now experiencing a renaissance, with psychedelic drugs such as LSD and psilocybin currently being investigated as new treatment options for conditions such as PTSD, treatment-resistant depression, and traumatic brain injury.

Equipped with new technologies that did not exist during the first psychedelics research movement, today’s researchers are keen to discover exactly how these psychedelic substances affect the brain.

Earlier this year, researchers at the University of Cambridge used functional magnetic resonance imaging (fMRI) scans of the brain to study how the human brain functions after taking LSD. They found that the hallucinogenic drug was able to weaken the relationship between the brain’s anatomical structure and its functional connectivity, effectively “freeing” the brain to explore new connectivity patterns.

Researchers have also recently explored the safety of LSD with respect to the brain, with a review from scientists at the University of Basel finding LSD to be “safe in regard to acute psychological and physical harm in healthy subjects” in controlled clinical settings.


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