By Andrew Bontemps
Original article: https://www.science.org/doi/10.1126/science.adf0435
“Perspectives” article: https://www.science.org/doi/10.1126/science.adg2989
Maxemiliano Vargas and colleagues from UC Davis and Medical College of Wisconsin recently released a paper describing some of the interesting ways that psychedelics work in the brain, and how the effects can support brain plasticity and provide some antidepressant effects. Using some cool molecular biology and mouse-model work they were able to examine how psychedelics impact neurons and the similarities and differences between psychedelics and serotonin, a common neurotransmitter. Read on to find out how serotonin and psychedelics affect the brain.
… the brain can be changed or molded in terms of its structure and function. The brain is considered “plastic” because connections (called synapses) can be formed, erased, or reorganized to form new pathways
Before we get too far in though, let’s define some key terms that we’ll use throughout this article. First, when we talk about plasticity, we mean that the brain can be changed or molded in terms of its structure and function. The brain is considered “plastic” because connections (called synapses) can be formed, erased, or reorganized to form new pathways (neat, right?). Second, psychedelics are a drug class that have historically been known to produce feelings of euphoria, visual hallucinations, and a greater appreciation of musical groups like the Grateful Dead or Phish (if you don’t get this joke, go ask your dad or nearest fatherly figure). They tend to produce these effects by acting on the serotonin (5-hydroxytryptamine [5-HT]) system of the brain, though their exact effects are not well known. With those definitions covered, let’s talk about what the authors set out to accomplish in their experiments.
What did the researchers do?
Previous research has shown that the activation of certain serotonin receptors, also known as 5-HT2ARs, is connected to increased brain plasticity. However, it’s unclear why some molecules that bind this receptor increase plasticity, but others don’t. Surprisingly, the authors note that serotonin can bind at 5-HT2AR sites but doesn’t produce the same kind of plasticity-inducing effects as psychedelics do. Given that serotonin cannot passively enter cells by itself, the authors questioned whether something known as location bias — when different signals are sent based on the location of a receptor site — might be involved in the different effects produced by serotonin and psychedelics. So, how did they do that?
How did the researchers do that?
The authors tested their theories through multiple different experiments. First, they showed that psychedelics actually produce spinogenesis — the growth of dendrite spines on neurons — by giving psychedelics to normal mice and mice that had been genetically modified to not have 5-HT2ARs. Then, they checked the neurons of the mice 24 hours later and found that mice with 5-HT2ARs had greater dendrite spine density than those without. This greater dendrite spine density is an indication of greater brain plasticity. Next, the authors wanted to check how different kinds of chemicals that have a similar structure to serotonin might affect spinogenesis differently. To do this, they took lots of mouse brain cells and applied ketamine — which they used as a positive control because they already knew that it would produce spinogenesis — as well as serotonin, tryptamine, and some other similar chemical compounds separately to clusters of cells. They found that a specific class of psychedelic compound, known as N,N-dimethyl compounds, produced the greatest increase in dendritic spines and, therefore, the most potential neuroplasticity. A distinguishing feature of the N,N-dimethyl compound class is their ability to quickly pass through the cell membrane. This suggested to the authors that the spinogenesis effect was due to 5-HT2ARs inside the neurons, rather than on the external surface. Following up on their hypothesis, they used a fluorescent staining technique to show that 5-HT2ARs were indeed within the cell, mostly found near the cells’ Golgi apparatus.
Let’s review. So far, the authors have found that 1) psychedelics produce increased dendritic spine growth, 2) they do so by acting at 5-HT2AR sites, and 3) the 5-HT2AR sites seem to be mostly inside the neurons. They then decided to test whether they would see the same kind of spine growth if they made it difficult for psychedelics to pass into the cell and bind to the 5-HT2ARs inside the cell. To do this, they took dimethyltryptamine (DMT), psylosin, and ketanserin (similar to psilocybin and ketamine, respectively) and gave them an ionic charge to prevent them from passing through cell membranes. After making sure the charged molecules would still bind to 5-HT2ARs, they then examined whether the charged psychedelics could produce the same effects on cells as their non-charged counterparts. They found that the psychedelics that could not enter neurons did not produce spine growth. This further suggested that spine growth may only occur if the psychedelics bind inside the cell.
They found that the psychedelics that could not enter neurons did not produce spine growth. This further suggested that spine growth may only occur if the psychedelics bind inside the cell.
The authors also tested what would happen if serotonin, which is normally too big to enter neurons, could enter a neuron through the use of a serotonin transporting protein. When serotonin was brought into the cell using the transporter protein, they saw the same levels of spinogenesis that the other psychedelics produced. Lastly, the researchers knew from previous studies that ketamine can produce antidepressant effects and wanted to see if they could reproduce those same antidepressant effects using transported serotonin. So, they genetically modified mice so that some had the serotonin transporter protein, allowing serotonin to enter neurons, and some didn’t. Compared to the mice without the serotonin transport protein, the mice with the serotonin transport protein showed a strong antidepressant-like effect when administered a serotonin-releasing chemical. This means that serotonin would act like a psychedelic if it were able to enter a neuron, but it normally doesn’t because it’s too big.
What do these results mean?
So, what does all of that mean? First, these results tell us that psychedelics seem to produce some of their effects by entering cells and binding at 5-HT2ARs inside the cell rather than on the outer surface. It also explains why serotonin doesn’t cause the same effects as other psychedelics with regard to dendrite growth, because it’s too big to pass across the cell membrane by itself. In addition to the main findings, the authors also note that the molecules that make it into the cell seem to stick around for a bit, continuing to bind to receptors in the cell and promoting dendrite growth, even after the drug has been removed elsewhere in the body. They speculate that this may be because the 5-HT2ARs are found near the Golgi apparatus, but more research is needed to confirm their hunch. This study also raises some questions: Why do we have these 5-HT2ARs inside the cells if serotonin can’t get to them? If serotonin can’t activate these receptors, what do we have in our bodies naturally that can? Is there some kind of transport protein that helps the serotonin across the cell membrane, or is there another molecule altogether, like one of the endogenous psychedelics (e.g. Barker, et al., 2012)?
… psychedelics seem to produce some of their effects by entering cells and binding at 5-HT2ARs inside the cell rather than on the outer surface.
While psychedelic compounds do seem to have some very exciting effects, they can also potentially be harmful and deserve to be treated with care. For example, a recent systematic review of negative impacts of psychedelics reported that common side effects of psilocybin included anxiety, confusion, nausea, and psychological discomfort including sensations like “feeling trapped” (Breeksema, et al., 2022) Likewise, they found that LSD was related to “feeling cold” and anxiety. Even under controlled conditions like those reviewed by Breeksema and colleagues (2022), psychedelics can have potentially serious side effects, which is one of the many reasons they deserve future study.
Additionally, psychedelics remain classified as a Schedule I drug at the federal level (United States Department of Justice, 2023), the strictest designation with no currently accepted medical use. However, many researchers push back against the classification (e.g., Nutt, et al., 2023). Due to the Schedule I classification, it has been historically very difficult for scientists to do any kind of research on Schedule I substances (Andreae, et al., 2016; Congress, 2022b). Recently, however, the federal government seems to be allowing more researchers to study controlled substances, for example, through the passage of the Medical Marijuana and Cannabidiol Research Expansion Act in 2022, provided that they can show how they will monitor participant use and keep track of the substances within their labs (Congress, 2022a). Even with stricter policies in place, we learned a lot about the brain and how it works both while drugs are present, and normally (e.g,. Vollenweider & Preller, 2020; Nutt, et al, 2023), and will continue to learn even more as policies and attitudes change.
If you have any questions or want to talk about it, drop a line in the comments below.
Written by Andrew Bontemps
Illustrated by Kayla Lim
Edited by Lauren Wagner, Chris Gabriel, and Gabrielle Sarlo
Andreae, M. H., Rhodes, E., Bourgoise, T., Carter, G. M., White, R. S., Indyk, D., … & Rhodes, R. (2016). An ethical exploration of barriers to research on controlled drugs. The American Journal of Bioethics, 16(4), 36-47.
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