Psychedelic drugs such as lysergic acid diethylamide (LSD), N,N-Dimethyltryptamine (DMT), and psilocybin, have been receiving attention from scientists and researchers due to evidence that suggests they have positive effects on the brain’s neuroplasticity. Neuroplasticity is the ability for the brain to adapt to new stimuli or damage by re-wiring neural pathways to form new connections. The brain’s neuroplasticity is utilized during the process of learning, forming new memories, or recovering from neurological damage such as head trauma or a stroke. Some brain disorders, such as Alzheimer disease and Parkinson disease, are suggested to be a result of a lack of or diminished neuroplasticity (Rugnetta, 2023).

For a drug to alter neuroplasticity, this would mean that it would have to enhance or stall the brain’s ability to adapt to incoming changes. Recent studies in psychiatry suggest that psychedelic drugs do promote molecular and cellular adaptations that are associated with neuroplasticity. These changes can occur with a single dose of the drug and result in the increase of neurogenesis, the formation of neurons in the brain. In mice exposed to psilocybin, the ability to learn and form memories seems to improve, which was attributed to the neurogenesis effects of the drug. It was also noted that lower dosages of the psychedelics seemed to have a greater effect on neuroplasticity than it did at higher dosages (de Vos, Mason, Kuypers, 2021).

The 5-HT2A receptor is a subset of the 5-hydroxytryptamine (5-HT) receptors, which consists of all serotonin receptors. These receptors can be found throughout the central nervous system as well as the brain. They are typically located on the cell surface as a transmembrane protein, but sometimes they can be found within the cell (Wikipedia Contributors, 2023a).

LSD, DMT and psilocybin all bind to various serotonin receptors. LSD is able to interact with brain cells through their 5-HT2A and 5-HT2B receptors (National Institutes of Health, 2017). Similarly, DMT is known to bind to the 5-HT1A, 5-HT2A, and 5-HT2C serotonin receptors, as well as the sigma-1 and G-protein-coupled trace amine receptors (Erowid, 2000). The sigma-1 receptor is a transmembrane protein found in the endoplasmic reticulum, and is associated with certain psychological disorders, such as clinical depression, schizophrenia, and bipolar disorder (Wikipedia Contributors, 2023b). When psilocybin is converted into psilocin in the body, it binds strongly to 5-HT2B, 5-HT7, and 5-HT1D receptors (Wikipedia Contributors, 2023c).

Ergolines, tryptamines, and phenethylamines are three classes of agonists that bind to the 5-HT2A receptor (Wikipedia Contributors, 2023a). Multiple psychedelic drugs fall into these classes, such as LSD, which is a derivative of ergoline (Wikipedia Contributors, 2023d). Since serotonin is derived from the amino acid tryptophan (Wikipedia Contributors, 2023e), it acts as a tryptamine agonist of the 5-HT2A receptor.

The serotonin receptors are responsible for many psychological and biological functions, such as cognition, appetite, mood, and sleep (Wikipedia Contributors, 2023f). A lack of serotonin in the brain is agreed to be the cause of clinical depression; this is why selective serotonin reuptake inhibitors are used as antidepressants, as they allow available serotonin to persist in the brain. It is suggested by an article in Live Science that psychedelics may be a treatment for depression, as they are able to access serotonin receptors inside the cell, which serotonin itself cannot (Lanese, 2023).

In the research paper published in the Science journal, referenced by the Live Science article, findings indicate the reasons why serotonin is not as effective as psychedelics at altering neuroplasticity. The importance of this is that our current understanding of depression and other mental illnesses is that they are a result of a decrease in dendritic arbor complexity, the length and number of branches on the neural cell body. It follows that drugs that promote neuroplasticity, known as psychoplastogens, may be able to treat these mental illnesses by increasing the number of dendrites on each neuron. Specific psychoplastogens of interest are serotonergic psychedelic drugs, such as LSD, DMT, and psilocybin, that bind to the cell’s 5-HT2A receptors (Vargas et al., 2023). Why these drugs were so successful at altering neuroplasticity, despite binding to the same receptors as serotonin, was one of the questions that the researchers sought to answer.

The researchers discovered that non-polar, or lipophilic, agonists were more likely to result in neuroplastic effects than polar agonists to the 5-HT2A receptors. This finding is what made the researchers speculate that the 5-HT2A receptors responsible for neuroplasticity were inside the cell. To test this, they used various derivatives of tryptophan on the embryonic cortical neurons of rats. Each of these derivatives varied based on levels of N-methylation, the replacement of hydrogen atoms in the amine group with a methyl group. As N-methylation increased, the polarity of the molecule decreased, such that serotonin was more polar than N-methyltryptamin, and N-methyltryptamin was more polar than DMT. In the article’s first figure, it was shown that less polar molecules were able to produce greater effects in neuroplasticity in the rat neurons. In particular, DMT was shown to significantly increase the dendritic arbor complexity of these neurons, evident by the greater number of dendrites visible in the microscopic images of rat neurons treated with DMT compared to rat neurons treated with serotonin.

Considering that polar molecules like serotonin do not promote neuroplasticity, the hypothesis that neuroplasticity promoting receptors might be inside the cell makes sense based on what we discussed in class about the plasma membrane. Serotonin’s difficulty to bind to intracellular 5-HT2A receptors is likely because the polar heads of phospholipids in the neuron cell’s outer membrane would repel polar molecules, making it difficult for these molecules to diffuse through without the help of a serotonin transporter (SERT) protein.

Through the use of a fluorescent blue dye, particularly Cellbrite Steady, on human embryonic kidney (HEK293T) and cortical neuron cells, the researchers were able to identify the location of the 5-HT2A receptors. In the article’s second figure, Microscopic imagery of the different cells shows bright white spots, the result of high concentrations of the dye in that location which indicates the presence of intracellular 5-HT2AR. Compared to the HEK293T cells, the intracellular 5-HT2AR were closer to the golgi apparatus, which research suggests is another location for G-protein-coupled receptor signalling.

It is still possible for serotonin to promote neuroplasticity, however. Through a process called electroporation, an electric current is applied to the cell membrane which changes its polarity and opens pores that allow serotonin to enter and bind to intracellular 5-HT2A receptors. This applies to other polar molecules as well, such as N,N,N-trimethyltryptamine (TMT), psilocybin (PSY), and methylated ketanserin (MKTSN). In the article’s third figure, it is shown that TMT and psilocybin increased the number of dendritic crossings after electroporation, indicating that they were able to enter the cell and affect neuroplasticity. For nonpolar molecules such as DMT and psilocin, there was very little change in dendritic arbor complexity with or without electroporation. To clarify these results, (TMT) benefits from electroporation because it is a polar molecule even though it is a product of N-methylation, as it has too many methyl groups to be nonpolar; as well, ketanserin and methylated ketanserin are 5-HT2A antagonists, so their binding to the receptors would not result in an increase in dendritic arbor complexity.

Typically, SERT proteins are found in the pre-synaptic terminals of neurons, where they exist in small quantities; however, DNA can be introduced to the neuron to make it express more of the SERT proteins across its membrane. This allows serotonin to enter the cell and increase dendritic arbor complexity; however, this can be prevented through the use of antidepressants drugs such as citalopram, as the researchers demonstrated. Citalopram is an SSRI, which blocks the SERT proteins and prevents serotonin from entering the cell. Despite SERT proteins being blocked by citalopram, DMT can still access the cell as it can diffuse across the cell membrane.

Thus far all the researcher’s tests were performed in vitro. To measure the antidepressant effects of dendritic arbor complexity in living organisms, the researchers took wild type mice and injected them with an adeno-associated virus that would cause some mice to express either a control protein or more SERT proteins. After three weeks, the mice were given a forced swim test to determine the length of time for which they spent immobile; here, longer times indicate depressive behavior. For both sets of mice, there was very little difference in FST results. However, when these mice were exposed to para-chloroamphetamine (PCA), a selective serotonin-releasing agent, the mice with a greater expression of SERT proteins were immobile for less time than those expressing the control protein, indicating that they experienced an antidepressant effect. It is worth noting that the SERT positive mice also experienced a head-twitch response (HTR) after receiving PCA, which is associated with the hallucinogenic effects of psychedelics. After the test, it was found though microscopic images of the rodent neurons that the SERT positive mice had more dendritic spines than the control mice, indicating that the serotonin from the PCA increased dendritic arbor complexity (Vargas et al., 2023).

The results of this study propose interesting implications about neuroplasticity, the nature of depression, and the purpose of intracellular receptors. The findings suggest that intracellular receptors are as important as membrane receptors in terms of responses to drugs. Because of their effects on neuroplasticity, researchers may decide to explore psychedelics or intracellular serotonin as treatments for depression. Care must be taken as it appears that the same receptors associated with neuroplasticity are also associated with the head-twitch response in mice, which may indicate a hallucinogenic experience. The cause of hallucinogenic effects and their relation to the intracellular serotonin receptors would need to be explored in order to assess possible risks of this treatment.

References

Rugnetta, M. (2023). Neuroplasticity. Britannica, https://www.britannica.com/science/neuroplasticity.

de Vos, C., Mason, N., Kuypers, K. (2021). Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. Frontiers in Psychiatry, https://doi.org/10.3389%2Ffpsyt.2021.724606.

Wikipedia Contributors. (2023a). 5-HT2A receptor. Wikipedia, https://en.wikipedia.org/wiki/5-HT2A_receptor.

National Institutes of Health. (2017). Protein structure reveals how LSD affects the brain. NIH, https://www.nih.gov/news-events/nih-research-matters/protein-structure-reveals-how-lsd-affects-brain.

Erowid. (2000). DMT Basics. Erowid, https://www.erowid.org/chemicals/dmt/dmt_basics.shtml.

Wikipedia Contributors. (2023b). Sigma-1 receptor. Wikipedia, https://en.wikipedia.org/wiki/Sigma-1_receptor.

Wikipedia Contributors. (2023c). Psilocybin. Wikipedia, https://en.wikipedia.org/wiki/Psilocybin.

Wikipedia Contributors. (2023d). Ergoline. Wikipedia, https://en.wikipedia.org/wiki/Ergoline.

Wikipedia Contributors. (2023e). Serotonin. Wikipedia, https://en.wikipedia.org/wiki/Serotonin.

Wikipedia Contributors. (2023f). 5-HT receptor. Wikipedia, https://en.wikipedia.org/wiki/5-HT_receptor.

Lanese, N. (2023). Psychedelics may treat depression by invading brain cells. Live Science, https://www.livescience.com/psychedelics-may-treat-depression-by-invading-brain-cells.

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., et al. (2023). Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors. Science 379, 700-706. https://doi.org/10.1126/science.adf0435