Chemical Reactivity Parameters to Analyze Psychedelics: How Do We Explain the Potency of the Drugs?

Psychedelics are psychoactive substances that produce changes in thoughts and feelings and modifications in perceptions of reality. The most potent psychedelic is also the first semisynthetic hallucinogen (lysergic acid diethylamide). Psychedelics have been investigated for decades because of their potential therapeutic effects in the treatment of neuropsychiatric diseases and also because these drugs are useful in controlling addictions to other substances. In this investigation, we analyze 27 psychedelic molecules. These compounds are serotonergic psychedelics; that is, they are serotonin agonists. We analyze the electron transfer properties to better understand the mechanism of action of these substances. We found that the electron acceptance capacity is related to the potency of the drugs: the best electron acceptor is also the most potent drug. We also used global softness as a parameter of reactivity. Molecules with greater global softness are more polarizable and also have greater potency. These results are useful to continue our understanding of the mechanism of action of psychotropic drugs.