LSD alters perception via serotonin receptors

January 26, 2017

Science Daily/University of Zurich

Researchers from UZH have discovered how the perception of meaning changes in the brain under the influence of LSD. The serotonin 2A receptors are responsible for altered perception. This finding will help develop new courses of pharmacotherapy for psychiatric disorders such as depression, addictions or phobias.

Humans perceive everyday things and experiences differently and attach different meaning to pieces of music, for instance. In the case of psychiatric disorders, this perception is often altered. For patients suffering from addictions, for instance, drug stimuli are more meaningful than for people without an addiction. Or patients with phobias perceive the things or situations that scare them with exaggerated significance compared to healthy people. A heightened negative perception of the self is also characteristic of depressive patients. Just how this so-called personal relevance develops in the brain and which neuropharmacological mechanisms are behind it, however, have remained unclear.

Researchers from the Department of Psychiatry, Psychotherapy and Psychosomatics at Zurich University Hospital for Psychiatry now reveal that LSD influences this process by stimulating the serotonin 2A receptor, one of the 14 serotonin receptors in the brain. Before the study began, the participants were asked to categorize 30 pieces of music as personally important and meaningful or without any personal relevance. In the subsequent experiment, LSD altered the attribution of meaning compared to a placebo: "Pieces of music previously classified as meaningless suddenly became personally meaningful under the influence of LSD," explains Katrin Preller, who conducted the study in conjunction with Professor Franz Vollenweider and the Neuropsychopharmacology and Brain Imaging research team.

LSD works via the serotonin 2A receptors

Such excessive or exaggerated attributions of meaning to experiences and environmental stimuli occur in various psychiatric disorders. Conversely, a coherent self depends on a functioning network of so-called cortical mid-brain structure, as more recent studies reveal. According to this, the network is impaired in various psychiatric disorders. "LSD now seems to affect this very network and influence the experience of meaning," explains Preller.

With the aid of functional magnetic resonance imaging (fMRT), the scientists were also able to demonstrate that study participants attached greater meaning to previously irrelevant stimuli after taking LSD. If, on the other hand, the serotonin 2A receptor was blocked pharmacologically before LSD was taken, all other psychological changes triggered by LSD were also normalized. "This was very surprising," says Preller. "After all, studies on animals revealed that LSD also stimulates other receptors, such as the dopamine D2 system." It was previously assumed that this might be responsible for the euphoria triggered by LSD and that different receptor systems were involved in the development of experiencing meaning. The results of the current study, however, clearly indicate the key role of the serotonin 2A receptor in both the subjective experience under LSD and the changes in brain activity revealed using fMRT.

Possible approaches for courses pharmacotherapy to treat psychiatric problems

This observation sheds light on how LSD affects the brain neuropharmacologically and especially how the pharmacology of meaning perception works. While the serotonin 2A receptor seems to be responsible for generating new meaning, the dopamine system might regulate the relevance of stimuli we generally deem important. These results may therefore one day benefit people suffering from psychiatric disorders characterized by an altered perception of meaning, such as depression, phobias and addictions.

https://www.sciencedaily.com/releases/2017/01/170126123127.htm

Answers to how our brains make meaning, with the help of a little LSD

January 26, 2017

Science Daily/Cell Press

We all have particular experiences or particular things -- a favorite song, for example -- that mean much more to us than others. Now, researchers who've studied how perceptions of meaning change when people take the psychedelic drug known as LSD have traced that sense of meaningfulness to particular neurochemicals and receptors in the brain. The findings are reported in Current Biology on January 26.

The findings add to our fundamental understanding of the human experience. They also point to potentially new targets for drugs to treat psychiatric illnesses or phobias, which come with abnormalities in the attribution of personal relevance to particular sensory experiences or cues, the researchers say.

"Our results increase our understanding of how personal relevance attribution is enabled in the brain," says Katrin Preller of the Zürich University Hospital for Psychiatry. "[We now know] which receptors, neurotransmitters, and brain regions are involved when we perceive our environment as meaningful and relevant."

Earlier studies showed that LSD alters the attribution of meaning and personal relevance to the environment, Preller explains. LSD also changes the way people perceive themselves, as the distinction between the self and the world outside the self blurs. But it wasn't clear exactly what parts of the brain and which neurochemicals were responsible.

Preller and colleagues first confirmed the usual effects of LSD on study participants' state of consciousness, mood, and anxiety in the lab. They found that those psychedelic effects of LSD were erased when participants took a second drug called ketanserin that blocked the ability of LSD to act on serotonin receptors known as 5-HT2ARs. That finding came as something of a surprise because LSD is also known to stimulate dopamine receptors, Preller says.

To explore LSD's influence on the way people attribute meaning to things in their world, the researchers asked participants taking a placebo, LSD, or LSD plus ketanserin to rank the meaning attached to a series of songs. Some of those songs were ones that participants told the researchers were particularly meaningful to them. Others were either neutral or without meaning.

The researchers found that musical pieces that were previously meaningless to participants took on special meaning when those individuals were under the influence of LSD. That effect was diminished when participants were given the second drug to counteract LSD's effects on the brain's serotonin receptors. Brain imaging studies also linked those changing attributions of meaning to particular brain areas.

"By combining functional brain imaging and detailed behavioral assessments using a specific experimental paradigm to investigate personal relevance or meaning of music pieces, we were able to elucidate the neurobiological correlates of personal relevance processing in the brain," Preller says. "We found that personal meaning attribution and its modulation by LSD is mediated by the 5-HT2A receptors and cortical midline structures that are also crucially involved in enabling the experience of a sense of self."

Preller says they now plan to explore whether they observe the same effects in response to visual or tactile stimuli. They also hope to explore the relevance of their findings to dysfunctional attributions of meaning in people with psychiatric disorders.

"Excessive stimulation of 5-HT2A receptors seems to underlay the experience of loosening of self/ego boundaries, disrupted self-referential processing and thus the related impairment of making meaning and attributing personal relevance to percepts and experiences seen in various psychiatric disorders," she says. "Therefore, it is important to consider this receptor subtype as potential target for the treatment of psychiatric illnesses characterized by alterations in personal relevance attribution."

A separate study in Cell on the structure of LSD and its receptor, and what this teaches us about the drug's potency, was also published on January 26.

This study was financially supported by grants from the Heffter Research Institute, the Swiss Neuromatrix Foundation, the Usona Institute, and the Swiss National Science Foundation.

https://www.sciencedaily.com/releases/2017/01/170126132544.htm