Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics

Abstract

Clinical studies suggest the therapeutic potential of psychedelics, including ayahuasca, DMT, psilocybin, and LSD, in stress-related disorders. These substances induce cognitive, antidepressant, anxiolytic, and antiaddictive effects suggested to arise from biological changes similar to conventional antidepressants or the rapid-acting substance ketamine. The proposed route is by inducing brain neuroplasticity. This review attempts to summarize the evidence that psychedelics induce neuroplasticity by focusing on psychedelics' cellular and molecular neuroplasticity effects after single and repeated administration. When behavioral parameters are encountered in the selected studies, the biological pathways will be linked to the behavioral effects. Additionally, knowledge gaps in the underlying biology of clinical outcomes of psychedelics are highlighted. The literature searched yielded 344 results. Title and abstract screening reduced the sample to 35; eight were included from other sources, and full-text screening resulted in the final selection of 16 preclinical and four clinical studies. Studies (n = 20) show that a single administration of a psychedelic produces rapid changes in plasticity mechanisms on a molecular, neuronal, synaptic, and dendritic level. The expression of plasticity-related genes and proteins, including Brain-Derived Neurotrophic Factor (BDNF), is changed after a single administration of psychedelics, resulting in changed neuroplasticity. The latter included more dendritic complexity, which outlasted the acute effects of the psychedelic. Repeated administration of a psychedelic directly stimulated neurogenesis and increased BDNF mRNA levels up to a month after treatment. Findings from the current review demonstrate that psychedelics induce molecular and cellular adaptations related to neuroplasticity and suggest those run parallel to the clinical effects of psychedelics, potentially underlying them. Future (pre)clinical research might focus on deciphering the specific cellular mechanism activated by different psychedelics and related to long-term clinical and biological effects to increase our understanding of the therapeutic potential of these compounds.

Keywords: cellular neuroplasticity; functional neuroplasticity; molecular neuroplasticity; psychedelics; structural neuroplasticity.

Figure 1

Mechanisms of neuroplasticity. Schematic representation of the different mechanisms of neuroplasticity at a molecular and (sub)cellular level. Neuroplasticity at a molecular level affects intracellular signaling pathways, gene transcription, and protein synthesis. At a cellular level, neuroplasticity occurs at the subcellular levels of neurogenesis, dendritogenesis, and synaptogenesis. The neuronal changes of neurogenesis and dendritic changes alter the structural characteristics of the neuron: structural plasticity. Synaptogenesis involves functional changes: functional plasticity. LTP, long-term potentiation; LTD, long-term depression.

Figure 2

Evaluation of psychedelics' influence on cellular and molecular neuroplasticity in preclinical and clinical studies. Schematic overview of the current methods to study the neuroplastic effects of psychedelics at a molecular and cellular level. NSCs, Neural stem cells; iPSCs, induced pluripotent stem cells.

Figure 3

Flow diagram illustrating the selection and review processes of the systematic review.

Figure 4

Proposed mechanism of action of cellular and molecular effects of serotonergic psychedelics. Schematic and simplified overview of the intracellular transduction cascades in the PFC induced by 5-HT2AR activation by psychedelics. When activated by psychedelics, the 5-HT2AR can activate multiple signaling cascades by coupling to G-proteins. These can activate PLC or PLA₂ signaling, both leading to modulations in synaptic plasticity. In addition, glutamate and TrkB activation stimulate AMPAR trafficking. BDNF also activates mTOR through TrkB, resulting in stimulated synaptic plasticity. 5-HT, Serotonin; 5-HT2AR, Serotonergic 2A receptor; Akt, Protein kinase B; AMPAR, α-amino-3-hydroxy-5-methyl-4-isozalopropionic acid receptor; BDNF, Brain-derived neurotropic factor; C/EBP-β, CCAAT enhancer binding protein; CAMK2, Ca²⁺/calmodulin-dependent protein kinase; CREB, cyclic AMP-responsive element-binding protein; DAG, Diaglycerol; ERK 1/2, extracellular regulated kinase 1/2; Iκβ-α, inhibitor of nuclear factor kappa B alpha; IP₃, Inositol triphosphate; MAPK, mitogen-activated protein kinase; mTOR, Mammalian target of rapamycin; NFκβ-α, nuclear factor kappa B protein complex alpha; NMDAR, N-methyl-D-asparate receptor; PI₃K, Phosphatidylinositol-4,5-bisphosphate 3-kinase; PKA, Protein Kinase A; PLA₂, Phospholipase A₂; PLC, Phospholipase C; TrkB, Tropomyosin receptor kinase B.