The Effects of Psychedelics on Neuronal Physiology

Abstract

Psychedelics are quite unique among drugs that impact the central nervous system, as a single administration of a psychedelic can both rapidly alter subjective experience in profound ways and produce sustained effects on circuits relevant to mood, fear, reward, and cognitive flexibility. These remarkable properties are a direct result of psychedelics interacting with several key neuroreceptors distributed across the brain. Stimulation of these receptors activates a variety of signaling cascades that ultimately culminate in changes in neuronal structure and function. Here, we describe the effects of psychedelics on neuronal physiology, highlighting their acute effects on serotonergic and glutamatergic neurotransmission as well as their long-lasting effects on structural and functional neuroplasticity in the cortex. We propose that the neurobiological changes leading to the acute and sustained effects of psychedelics might be distinct, which could provide opportunities for engineering compounds with optimized safety and efficacy profiles.

Keywords: 5-HT2A receptor; DMT; LSD; hallucinogen; neuroplasticity; psilocybin; psychedelic.

Figure 1.

Polypharmacology of psychedelics. (a) Structures of several psychedelic drugs with tryptamine, phenethylamine, and ergoline frameworks highlighted in blue, red, and purple, respectively. Panel adapted with permission from Reference ; copyright © 2022, Springer Nature America, Inc. (b) Radioligand binding profiles for prototypical members of the phenethylamine (DOI), tryptamine (DMT), and ergoline (LSD) families. Red boxes indicate Ki values <1 μM, pink boxes indicate Ki values 1–10 μM, and white boxes indicate Ki values >10 μM using either agonist or antagonist radioligands. Dark gray boxes indicate data that are not available. Data obtained from the Psychoactive Drug Screening Program Ki Database with the exception of TAAR1 data. Data for TAAR1 were taken from Reference , with red boxes indicating >50% activation of rat TAAR1 following a 1 μM treatment, (c) Radioligand binding to 5-HT_2A receptors across the human brain. Panel adapted with permission from Reference . (d) Expression of 5-HT_2A receptors in the mouse brain. Panel adapted with permission from Reference ; copyright © 2010 Weber and Andrade. LSD, lysergic acid diethylamide; DMT, N,N-Dimethyltryptamine; DOI, 2,5-dimethoxy-4-iodoamphetamince; SERT, serotonin transporter; TAAR1, trace amine-associated receptor 1; AC, anterior cingulate cortex; Aud, auditory cortex; Ctx, cortex; Ent, entorhinal cortex; Hipp, hippocampus; Ins, insular cortex; M1, primary motor cortex; Orb, orbital cortex; PL, prelimbic cortex; Rh, rhinal cortex; S1, primary somatosensory cortex; S2, secondary somatosensory cortex; Str, striatum.

Figure 2.

Psychedelics promote structural neuroplasticity. (a) DOI, DMT and LSD promote dendritogenesis in vitro. Dendrite tracings and Sholl plots are shown. Panel adapted from Reference , reprinted with permission from Elsevier, (b) 5-MeO-DMT increases dendritic spine density in the prefrontal cortex of wild type, but not 5-HT_2AR knockout mice. Panel adapted with permission from Reference ; copyright © 2023, The American Association for the Advancement of Science, (c) Psilocybin produces long-lasting changes in dendritic spine density in vivo. Panel adapted with permission from Reference ; copyright © 2021, Alex C. Kwan. (d) DOI, and the non-hallucinogenic 5-HT_2AR agonist TBG, increase dendritic spine formation in the primary sensory cortex as measured by 2-photon imaging in vivo. Blue and red arrowheads indicate newly formed and eliminated spines, respectively. White arrowheads indicate filopodia. Panel adapted with permission from Reference ; copyright © 2020, David E. Olson, under exclusive license to Springer Nature Limited.

Figure 3.

Psychedelics impact neuronal activity, (a) 5-MeO-DMT increases cortical EPSCs in wild type, but not 5-HT_2AR knockout mice. Panel adapted with permission from Reference ; copyright © 2023, The American Association for the Advancement of Science. (b) Psilocybin increases hippocampal slice EPSPs. Panel adapted with permission from Reference ; copyright © 2021, National Academy of Sciences. 5-MeO, 5-methoxy-N,N-dimethyltryptamine; APV, 2-Aminophosphonovaleric acid; DNQX, 6,7-dinitroquinoxaline-2,3-dione; EPSP, excitatory postsynaptic potentials; KO, knockout; sEPSC, spontaneous excitatory postsynaptic currents; VEH, vehicle.

Figure 4.

Schematic overview of the putative molecular mechanisms of psychedelic drug action as well as the molecular-, cellular-, and circuit-level effects of psychedelics on neuronal physiology.