Modulating the Thermodynamics and Kinetics of Psychedelics at Serotonin Receptors via Terahertz Waves

Abstract Precise control over the thermodynamics and kinetics of receptor–ligand interactions is pivotal for manipulating physiological processes and developing targeted therapies. However, conventional pharmacological approaches often lack the spatiotemporal precision required for noninvasive in vivo modulation. Terahertz (THz) technology offers a promising alternative by using nonionizing electromagnetic radiation to specifically influence biomolecular vibrations. Here, we integrated molecular dynamics (MD) simulations with in vitro assays to investigate whether specific THz frequencies modulate the binding of the psychedelic ligands lysergic acid diethylamide (LSD) and psilocin to 5-hydroxytryptamine 1A receptor (5-HT1AR) and 5-hydroxytryptamine 2A receptor (5-HT2AR). Our simulations identified that irradiation at 42.4 and 48.6 THz selectively enhanced the vibrational modes of the conserved D3.32 carboxylate group, stabilizing its salt bridge with the ligand’s ammonium moiety and thereby increasing binding affinity. Consistent with this, in vitro experiments showed that these THz frequencies potentiated LSD- and psilocin-induced Gi signaling via 5-HT1AR and Gq signaling via 5-HT2AR. Furthermore, irradiation prolonged the predicted residence times in most receptor–ligand–frequency combinations, including psilocin at both receptors and LSD at 5-HT2AR, whereas 48.6 THz irradiation shortened the predicted residence time of LSD at 5-HT1AR. These kinetic effects were correlated with reduced flexibility of the extracellular loop 2 (ECL2). These findings provide an in vitro proof of concept that selected irradiation frequencies can modulate receptor-associated signaling and computationally predicted receptor–ligand interaction landscapes, opening a possible avenue for fundamental biophysical studies of physical-field regulation of receptor pharmacology.