Psychedelic chemistry: How small changes can have big effects

The Art of Rational Drug Design?

All classic psychedelic drugs activate the serotonin 5-HT2A receptor to elicit 'psychedelic' effects. But how they interact with the 5-HT2A receptor dictates how long and how strong their effects are.

• Here is LSD bound to the 'psychedelic' serotonin 5-HT2A receptor

Dr Alexander Shulgin, the "Godfather" of?MDMA,?developed hundreds of new psychoactive agents throughout his career and discovered their effects through self-experimentation.

His work highlights that very small changes in chemical structure can have profound effects on the dose, duration, and subjective experience of a psychedelic drug. In medicinal chemistry, this "tweaking" of chemical structure is known as?rational design.

For example, Shulgin hypothesised that modifying?mescaline?to form TMA would change its metabolism. Indeed,?TMA?was found to be about 3 times as potent as mescaline, and lasted ~30% longer.

Then, modifying TMA to?TMA-2?increased potency by 5-fold, and extended duration by another 50%.?

While adding?a bromine atom to TMA-2 formed?DOB?- an incredibly potent psychedelic with a dose of just 1 mg lasting up to 30 hours! ??

At Psylo we are?using these and other medicinal chemistry techniques to develop next-generation psychedelics that are optimized for therapeutic use!

Written by Dilara Bahceci, PhD