Title : Psychedelic drugs – safety problems in pregnancy
Abstract:
Psychedelic drugs acting upon the serotonergic receptors are currently considered to be not only substances of abuse, but also the hope of new therapies of mental problems such as depression, PTSD and eating disorders; pain; inflammations or even asthma. The main challenge in this field is to design new compounds that would give similar therapeutic effects but without hallucinogenic activity. There are hundreds new compounds designed to have such properties, but not everything is known so far about their safety, especially for potential unintentional users – offspring during pregnancy and breastfeeding, susceptible to risks associated with maternal drug use or abuse. In this research 250 new compounds derived from 3 main psychedelic substances – LSD, mescaline and psilocin were investigated in the context of their ability to cross the placenta and to interfere with placental enzymes responsible for deactivation of harmful xenobiotics - glutathione-s-transferase (GST) and N-acetyl transferase 2 (NAT-2). Novel QSAR models of fetus-mother partition coefficients (FM) were used to estimate this property for studied compounds. Models were developed using calculated physico-chemical descriptors describing molecules’ size, lipophilicity and electronic properties using Multiple Linear Regression and LASSO regression methods. It was confirmed that the ability of compounds to cross the placenta is related to their ability to be absorbed from the gastro-intestinal tract estimated according to very simple, yet useful empirical guidelines (Lipinski’s Rule of 5). It turned out that almost all the studied compounds (250 psychedelics and their derivatives) are likely to cross the placenta easily by passive diffusion. Four compounds (psilocybin, psilocin, mescaline and LSD) were investigated by molecular docking to estimate their affinity for the GST and NAT-2 enzymes. These affinities are relatively high which suggests the possible ability of these compounds to interfere with studied enzymes, but further studies are needed to confirm this hypothesis (e.g. by dynamic simulation methodology). To conclude, new compounds from the chemical families of tryptamines, phenylethylamines and lysergic acid derivatives (structurally related to psilocin, mescaline and LSD, respectively) are likely to cause issues when used during pregnancy - but further, more detailed research in this area is recommended.
