How acid warps your thoughts and feelings

It’s been eight decades since Swiss chemist Albert Hofmann first cooked up the psychedelic drug lysergic acid diethylamide – LSD or “acid” – and half a century on from its heyday during the 1960s counterculture, how LSD messes with our brain is still little understood.

But two new studies published today help to reveal those brain regions affected and neurochemical receptors responsible for LSD’s mind-altering effects.

In the first study, published in Current Biology, a team of researchers in Switzerland looked at how LSD affects the way in which we imbue things – a smell wafting from a restaurant, the face of a person walking down the street, a song heard on the radio – with a sense of personal relevance.

“We do this all the time, probably most of the time unconsciously,” says neuroscientist and study co-author Katrin Preller from the University of Zurich.

On LSD – as well as in psychiatric disorders such as schizophrenia and addiction – this sense of personal meaning increases. Preller and her colleagues wanted to know why.

They enlisted volunteers to listen to music that was personally meaningful to them – music from their favourite band, perhaps – as well as music that held no special relevance.

When taking LSD, people consistently rated formerly meaningless tunes as being more meaningful.

The team used functional magnetic resonance imaging to zero in on brain regions responsible and found that cortical midline structures – a network of connected brain regions thought to be crucial to building our sense of self – were key to LSD’s ability to imbue added meaning.

At the molecular level, a single brain receptor – the serotonin 2A receptor – was responsible. Block the receptor – as the team did by giving participants a drug called ketanserin – and the meaningless songs remained meaningless.

Indeed, questionnaires completed by the study participants suggest that all of LSD’s wide-ranging psychological effects – from feelings of blissfulness or insightfulness to spiritual experiences and hallucinations – depend on the activity of this single receptor.

“It was kind of surprising,” says Preller, because LSD is known to interact with other receptors in the serotonin receptor family, as well as dopamine receptors.

Another long-standing puzzle surrounding LSD is that although it seems to clear from blood – and even the cerebrospinal fluid around the brain – in just a few hours, people can report hallucinations for a whole day. Work by a team of researchers in the US and published in Cell explains why.

The team crystallised the serotonin 2B receptor bound to LSD as a way of precisely examining how the two interact. The serotonin 2B receptor is closely related to, but better studied than the serotonin 2A receptor.

They found that LSD nestles into a pocket of the receptor and is then locked in place by a loop of the receptor that folds over the top like a lid. Once there, neither the lid nor the LSD can break free.

“The body has no means of clearing it from the brain, simply because the compound is really stuck in that receptor,” says structural biologist Daniel Wacker from the University of North Carolina at Chapel Hill, a co-author on the study.

But the study also provides a cautionary note for drugmakers looking to mimic LSD’s staying power, says Wacker. When the team deleted the receptor latch to see what would happen with fast-acting LSD, the receptor started working differently, activating molecules in only one of its two usual signalling pathways.

If you tinker with how long a drug docks on its target receptor, says Wacker, “you really need to look into whether or not you’re still getting the therapeutic effect” and not some unwanted side-effects.