Get Psyched! Psychedelic-Induced Neuroplasticity as a Therapeutic for Mental Illnesses
Written by Kalyani Seshan
Edited by Carolyn Chiu
April 5, 2024
Edited by Carolyn Chiu
April 5, 2024
Research
Psychedelic drugs like psilocybin, LSD, and ayahuasca are known for their hallucinogenic properties that alter perception, cognition, and mood1. Recreational, spiritual and therapeutic uses of these drugs have existed throughout history, but current research is focused on their therapeutic potential in mental illness, especially depression. Our brains contain millions of neurons with complex, branching structures called dendrites designed to receive signals like serotonin (5-HT) from other cells. Depression is linked to a loss of dendritic spines and is traditionally treated long-term with antidepressants like selective serotonin reuptake inhibitors (SSRIs)2. Recent evidence demonstrates that psychedelics can rapidly induce antidepressant-like dendritic spine growth in the cortex by activating serotonin receptors (5-HT2As), classifying them as psychoplastogens, or drugs that produce neuroplasticity3. But how? Serotonin itself has no hallucinogenic effects and cannot increase neuronal growth. Researchers at the Institute for Psychedelics and Neurotherapeutics at University of California, Davis have identified a group of 5-HT2As located within cells that could be key to understanding why certain psychedelics promote neuroplasticity, and if serotonin truly is the endogenous ligand for intracellular 5-HT2As in the cortex3.
To understand the mechanisms of neuroplasticity, confirming 5-HT2A involvement in its development is essential. Two groups of mice with and without 5-HT2As were given 5-MeO, a psychedelic related to N,N-Dimethyltryptamine (DMT). Spine density increased only in the mice with 5-HT2As, identifying the receptors as necessary in promoting neuroplasticity. The scientists also discovered that ligand structure can affect the change in spine density; the addition of methyl groups to the molecules’ structures makes them more lipophilic, allowing them to enter cells rather than solely bind to 5-HT2As on the cell membrane. This increased lipophilicity enhances the signals’ abilities to promote neuronal growth, indicating there must be a subset of intracellular 5-HT2As influencing the psychoplastogenic effects that psychedelics have in the brain.
Using cortical neurons, researchers next determined whether this group of receptors is involved in psychedelic-induced neuroplasticity; they altered the structure of membrane-permeable ligands, including DMT, psilocin (PSI), and ketanserin (KTSN), into membrane-impermeable molecules. When treating neurons with original and modified drugs, the membrane-permeable drugs increased dendritic spine density both when administered alone and with physical intervention via electroporation. Membrane-impermeable drugs, however, required physical intervention to cause any changes. Comparing them with serotonin, they discovered that unless allowed into the cell with electroporation or the addition of serotonin reuptake transporters (SERT), serotonin was unable to increase cortical dendrite growth. Taken together, these findings suggest that intracellular 5-HT2As are accessible to membrane-permeable psychoplastogens and that serotonin may not be their endogenous ligand.
The role of intracellular 5-HT2A receptors has been revealed to affect neuronal growth, and likely involves TrkB, AMPA receptors, and mTOR signaling in downstream mechanisms of psychedelic activity.3-4 Now, researchers must determine if psychedelics’ hallucinogenic properties are facilitated by 5-HT2As and if they are independent of dendrite growth induced by these other factors. These findings revolutionize our understanding of 5-HT2A receptors, as well as serotonin and psychedelic function, and highlight the therapeutic potential of psychedelics’ long-lasting, antidepressant effects.
References
1. Nichols DE. Psychedelics [published correction appears in Pharmacol Rev. 2016 Apr;68(2):356]. Pharmacol Rev. 2016;68(2):264-355. doi:10.1124/pr.115.011478
2. Qiao H, Li MX, Xu C, Chen HB, An SC, Ma XM. Dendritic Spines in Depression: What We Learned from Animal Models. Neural Plast. 2016;2016:8056370. doi:10.1155/2016/8056370
3. Vargas, M. V., Dunlap, L. E., Dong, C., Carter, S. J., Tombari, R. J., Jami, S. A., Cameron, L. P., Patel, S. D., Hennessey, J. J., Saeger, H. N., McCorvy, J. D., Gray, J. A., Tian, L., & Olson, D. E. (2023). Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors. Science (New York, N.Y.), 379(6633), 700–706. https://doi.org/10.1126/science.adf0435
4. Ly C, Greb AC, Cameron LP, et al. Psychedelics Promote Structural and Functional Neural Plasticity. Cell Rep. 2018;23(11):3170-3182. doi:10.1016/j.celrep.2018.05.022
Image Source: “Colorized 3D reconstruction of dendrites” by NIH Image Gallery licensed by CC BY-NC 2.0