LSD reveals its secrets

A long-standing pharmacological mystery surrounding hallucinogens may finally have been solved by a new US study. Javier Gonzalez- Maeso at Mount Sinai School of Medicine in New York, and colleagues have thrown new light on these unique psychedelic effects. 

’We know that hallucinogens act on serotonin 2A (5HT_2A) receptors in the brain. But so do a number of other drugs. The mystery was, why all drugs that activate those receptors don’t cause the same responses,’ team member Stuart Sealfon told Chemistry World. 

The study combined behavioural, biochemical and genetic testing, comparing the hallucinogen LSD with lisuride, a structurally similar drug that also acts on serotonin or 5HT_2A receptors but is not hallucinogenic.

They measured the behavioural response to both drugs in mice with and without the crucial receptors.

  ’Once we showed, with behavioural testing, that activation of this receptor is responsible for these hallucinogenic effects, we used cell cultures and measured the biochemical response of the cell to each drug,’ said Sealfon, who added that the study had been a massive undertaking. 

Biochemical tests showed that LSD and lisuride caused the activation of two different chemical signalling cascades within the cell. This led to the conclusion that activation of the same receptor can produce very different effects. 

’The 5HT_2A receptor itself can generate more than one response, like a switch with more than one "on" position,’ explained Sealfon. ’Hallucinogens cause the receptor to activate in a way that causes changes in the target neurons to lead to the characteristic neuropsychological responses.’  

Ursula D’Souza from the Institute of Psychiatry in London, UK said that the results were very interesting for the field. ’This information could be potentially valuable for the development of new drugs in neuropsychiatry,’ she said. 

Now, the researchers plan to study the whole receptor complex in more detail, ’to understand how it works as a multi-position switch and to figure out how these hallucinogen-specific signalling responses lead to an altered state of the neurons and to the behavioural changes we observe,’ said Sealfon.

Victoria Gill