Assessing the Potential Role of Astrocytes in Modulating the Neuroplastic Effects of Psychedelic Drugs

Abstract

The neuroplastic effects of classical psychedelics have been studied mostly through neuronal mechanisms.However, astrocytes may also be involved in the long-lasting neuroplastic effects of psychedelics because of their role in synaptic function and plasticity.This review examines if astrocytes could mediate or modulate psychedelic-induced neuroplasticity and evaluates the evidence supporting this possibility.Classical psychedelics produce different forms of neuronal plasticity at molecular, functional, and structural levels, including dendritic remodeling and synaptic changes.However, it is still not completely understood how these changes are regulated and maintained.Astrocytes regulate several of these processes, including neurotransmitter homeostasis, Ca²⁺ signaling, synaptic organization, metabolic support, and neuroimmune processes.Experimental evidence outside of psychedelic models showed that astrocytic signaling may influence serotonin-dependent synaptic plasticity and N-methyl-D-aspartate receptor-dependent long-term potentiation.Recent evidence shows that psilocin alters astrocytic proliferation, mitochondrial function, ATP, lactate, and glutamate release, while partial depletion of prefrontal astrocytes attenuates some behavioral responses to psilocybin.Psychedelics have also been shown to influence astrocyte-associated neuroimmune processes involved in stress-related fear.All together, these findings suggest that astrocytes may function alongside established neuronal mechanisms to influence the development, stabilization, or persistence of psychedelic-induced plasticity.However, current evidence does not establish astrocytes as necessary mediators of psychedelic-induced plasticity.There is a lack of direct experimental evidence showing that psychedelic exposure produces a defined astrocytic response that then leads to neuronal plasticity and, ultimately, to persistent behavioral or therapeutic effects.Future studies that selectively manipulate astrocytic pathways during psychedelic exposure while directly measuring neuronal plasticity and longer-term outcomes are needed to establish this causal relationship.Current evidence is therefore more consistent with a potential modulatory role for astrocytes than with an established mediating role in psychedelic-induced neuroplasticity.