|
Introduction
Tolerance to psychedelic drugs develops rapidly with repeated exposure, yet not uniformly across compounds. In humans, lysergic acid diethylamide (LSD) shows robust tolerance, whereas dimethyltryptamine (DMT) appears largely resistant despite acting on the same 5-HT2A receptor system. Tolerance is commonly attributed to downregulation of 5-HT2A receptors, although direct experimental evidence remains limited. Methods In a cross-scale approach, we here combined behavioural, physiological, and molecular measures. In rodents, shaking behaviour (head twitches, wet dog shakes) and temperature-dependent hyperthermia served as readouts of 5-HT2A activation. Repeated administration paradigms assessed tolerance to LSD, DMT, and the 5-HT2 selective drug DOB. Post-mortem radioligand binding and G-protein assays quantified 5-HT2A and glutamate receptor adaptations, with a focus on the frontal cortex. Complementary in vitro experiments in 5-HT2A-expressing cell systems examined receptor internalisation, phospholipase D activation, and transcriptional regulation. Results Repeated administration of LSD and DOB led to a rapid loss of behavioural effects. Tolerance, as indicated by frontocortical radioligand-binding assays, was associated with a decrease in 5-HT2A binding, 5-HT2 related G-protein coupling capacity, and/or glutamatergic adaptations. In contrast, repeated DMT administration neither produced tolerance in vivo nor reductions in G-protein coupling. Instead, an increase in 5-HT2A binding was observed. In cell systems, LSD and DOB/DOI induced 5-HT2A receptor internalisation, reduced receptor transcription, and activation of phospholipase D, an enzyme required for receptor internalisation, whereas DMT failed. Discussion Our data show that psychedelic 5-HT2A downregulation is evident across behavioural, physiological, and molecular levels. At the same time, DMT systematically differs, as it neither produces tolerance nor engages these processes. Differential tolerance to LSD and DMT is a hallmark of human psychedelia, implying that differences in 5-HT2A regulation may contribute to tolerance across species. Where such regulation is insufficient, compensatory glutamatergic downstream adaptations may occur. Given the central role of 5-HT2A mediated plasticity in psychopathology, differential receptor regulation may inform therapeutic deployment by anticipating whether repeated psychedelic stimulation leads to adaptation or sustained responsiveness. Media & dissemination: Behav Brain Res | Book chapter | PhD dissertation | ICPR 2016 | Mind Foundation | Conference abstracts (PharmTox Summit 2016 and DGPT 2012) Funding: Performance-Oriented Granting of Funding (LOM; Faculty of Medicine, Otto-von-Guericke University Magdeburg) Institution: Laboratory for Receptor Pharmacology, Institute for Pharmacology and Toxicology, Otto-von-Guericke University Magdeburg (Germany) How to cite: Buchborn T (2026). Differential tolerance to LSD and DMT occurs via 5-HT2A regulation. psyborn.com/lsd-dmt-tolerance-5-ht2a.
|