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Researchers Come Closer to Understanding How Psychedelics Effect Serotonin Receptors

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Researchers Come Closer to Understanding How Psychedelics Effect Serotonin Receptors

Floris Wolswijk, the founder of Blossom, breaks apart recent developments in psychedelic research in this monthly column in cooperation with Lucid News. Blossom is your go-to place to find insights on the latest psychedelic research and the companies bringing this into practice.

In the beginning, there was Freud. 

According to Freud’s theory of psychoanalysis, depression occurs due to processes in the unconscious mind. Bringing these processes to the surface can take many hours of psychotherapy. Psychoanalysis posits that transformation requires us to acknowledge our primal urges and subconscious desires, and subsequently develop the ability to handle them in a mature, reasoned, and contemplative manner. Though less prominent than it was in the early 1900s, psychoanalysis is still commonly practiced.

During the mid-20th century, the field of psychoanalysis was gradually replaced by an emerging understanding of the brain’s inner workings. Dilworth Woolley, who conducted research on LSD, proposed a novel idea in the field of neuroscience. He suggested that serotonin, a neurotransmitter initially discovered in the gastrointestinal system, might play a crucial role in the development of mental disorders.

Serotonin is a mood regulator, which means that it helps to regulate emotions, sleep, appetite, and pain. It is known to impact several regions of the brain that control mood, including the limbic system, which governs our emotional responses.

This mechanistic school of thought explains that depression transpires from neurotransmitter imbalances. These imbalances can be fixed with pills that increase the availability of serotonin. Billions of antidepressant prescriptions later, mixed results show success for some individuals, but no signs of depression decreasing in the population.

Around the turn of the century, research into psychedelics, equipped with the latest scientific tools, underwent a renaissance. Roland Griffiths and colleagues gave the “serotonin-like” molecules to participants diagnosed with life-threatening cancer and observed positive changes in mood.

Instead of imbalances, the psychedelic model proposes that depression is caused by a lack of neural flexibility. Making the brain more malleable could help solve depression. Studies tentatively show that psychedelics promote neuroplasticity – the ability to adapt to new situations.

Still, many questions remain about why psychedelics, changes in neurons, and even therapy more broadly work. New research by Maxemiliano Vargas and colleagues at UC Davis sheds new light on these questions.

Several experiments conducted by the UC Davis researchers highlight how psychedelics interact with serotonin receptors inside neurons, leading to neuroplasticity. This has implications for our understanding of psychedelics, and how they can help with mental health treatments, and therapy, more broadly.

The Pieces of The Neuroplasticity Puzzle

Most of your serotonin is produced in the gut, and only one to two percent is found in the brain and spine. In the brain, serotonin is a neurotransmitter, sending signals from one neuron to the next. Think of serotonin as a neighbor dropping by for a quick chat at the front door of the neuron.

Serotonin attaches to the neuron at the receptor site. Imagine this as the front door. Your house is actually quite the mansion and for this example, we’re looking specifically at doors 5HT2A and 5HT2B – the receptors of most interest. These receptors are called “serotonin receptors” because serotonin binds to these receptors which respond to their signals.

After serotonin finds the correct doors, it rings the doorbell, causing a chain reaction to happen inside the neuron. Basically, the neuron hears the bell and sends someone to answer the door where a quick chat with the neurotransmitter happens. Then serotonin goes on its way.

In 1956, Woolley recognized the “serotonin-like” behavior of LSD. When LSD was given to anesthetized dogs at various doses, the same pattern of changes in blood pressure was seen as when serotonin was administered.

They didn’t know it then, but LSD visited the same doors as serotonin (5HT2A and 5HT2B). But visiting the door isn’t enough. Without ringing the doorbell and getting a response from inside the house (a chain reaction happening within the cell), nothing happens. So how was LSD causing the same changes as serotonin?

This is where research by Daniel Wacker and colleagues at the University of North Carolina (UNC) in 2017 shed some more light. The UNC researchers described how LSD attaches to serotonin receptors, how it stays put, and what happens inside the neurons.

LSD binds to the serotonin receptor because it looks similar to serotonin. The receptors in our cells don’t particularly care if the molecule that comes along is exactly the one it usually responds to. In this case, LSD has the right shape to stick around, ring the doorbell and get a reaction from inside the cell.

LSD might resemble the friendly neighbor, but on closer inspection, it turns out to be the chatty one who likes to overstay their welcome. LSD binds to the serotonin receptors on the outside of a cell, but instead of leaving within milliseconds, as serotonin does, it sits there for about three and a half hours. Because of how the molecule is structured, LSD stays stuck on the receptor site, continually sending a signal to the cell. The neighbor misses every hint that you want to get on with your day.

A molecule’s structure helps determine its influence within a cell. Ketanserin is another molecule that visits the same doors as serotonin, but is structured differently. In experiments, ketanserin has been shown to block the effects of psychedelics, but isn’t psychedelic itself. Instead of someone opening the door and chatting right away, imagine someone standing around for a while, guarding the door. No one else is coming in, but inside none are the wiser.

If ketanserin leads to no meaningful effects, serotonin initiates a business-as-usual response in neurons. Several people inside the house hear the neighbor ring the doorbell, and the normal neuron activity occurs inside the cell. Another effect of serotonin is that it may increase the firing rate of the cell’s neurons. 

Back at the cells where LSD has firmly attached itself, something else is happening. Whilst the chatty neighbor is gossiping at the front door, the inside of the house overhears a flurry of rumors, leading to other unusual signals. These signals happen inside the cell and also lead to a higher neuron firing rate, sending housemates out to spread the word to other households.

This is what we knew in 2017. We knew what happened outside of the cell, and that it also led to changes inside the house. The difference between these outside-in signals between serotonin and psychedelics like LSD was our best explanation for why the acute psychedelic effects and long-term neuroplastic changes were observed.

The UC Davis paper looks at what happens when the psychedelics are inside the house.

Several Clever Experiments Show What Leads to Neuroplasticity

Since the 1960s, research has hinted that psychedelics promote neuroplasticity. Reviewing the literature in late 2022, Abigail Calder and Gregor Hasler from the University of Fribourg conclude, “The window of neuroplasticity appears to open within a few hours and may last a few days, although neuroplastic changes occurring during this time may survive for at least a month.”

Neuroplasticity refers to the brain’s ability to adapt to new experiences. When you’re learning a new language, new pathways (also called synapses – connections between neurons) are laid down. Neuroplasticity is ongoing, though generally believed to be strongest in children.

The best guess as to why psychedelics promote neuroplasticity was their effects on the outside of neurons. The UC Davis team wanted to test this. To do this, they first manipulated psychedelics to only be active on the outside, but not get into neurons. This was done by making them less fat-soluble.

Psychedelics are inherently fat-soluble, and fat-soluble molecules have the advantage of being able to cross the blood-brain barrier and slip inside cells. Imagine psychedelics as the smooth-talking date that is suddenly sitting on the couch. Without the fat solubility, they must do their magic at the front door.

No magic happened. The modified psychedelics still had their effects at the front door, and the same cascading chaos inside the house occurred. But no new neuronal connections were observed without the psychedelics getting inside the cell and attaching to the serotonin receptors. 

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Andrew Gallimore argues that the psychedelic (hallucinogenic) effects will still occur. “So, whilst psychedelics do need to activate intracellular 5HT2A receptors to have neuroplasticity effects, they don’t need to get inside the neuron to have psychedelic effects — they just need to be present (or accumulate) in sufficient concentrations around 5HT2A receptors, whether these are on the membrane or inside the neuron.”

Neuroplasticity After Non-Psychedelic Molecules?

The UC Davis team then asks the question the other way around: What if we let the non-psychedelic serotonin inside neurons? Through a process of electroportation, serotonin can move into the cell. When inside, the serotonin attached to the serotonin receptors and caused the neuroplastic effects normally seen with psychedelics only.

This is part of the research where more questions emerge. Is there a way of transporting non-psychedelic serotonin (or other molecules that activate the serotonin receptors) inside neurons and activating neuroplasticity? And will that physiological mechanism be enough for therapeutic effects, or does the psychedelic experience, at the psychological level, play a vital role in healing mental illness?

Another question is why psychedelics’ neuroplasticity effects last long after the molecules have left the outside of neurons. In their study, the UC Davis researchers explain that “Protonation of psychedelics within the Golgi leads to retention and sustained signaling, which results in neuronal growth, even after transient stimulation.” Translation: the molecules may stick around much longer inside a neuron.

Looking beyond psychedelics, the UC Davis team asks, “Given that the antidepressant mechanisms of ketamine and SSRIs have not been definitively established, it is intriguing to speculate that they also might promote cortical neuron growth by binding to intracellular targets.” Could all antidepressant effects boil down to increasing neuroplasticity?

The literature on talk therapy makes the same connection between therapy and the cognitive flexibility of depressed people. Those who followed a course of cognitive behavioral therapy (CBT) showed increased cognitive flexibility at the end of the study.

What Role Does the Acute Psychedelic Experience Play?

At the psychological level, a strong association is seen between aspects of the acute experience and long-term positive outcomes. A recent review by Samuli Kangaslampi from Tampere University synthesizes data from 44 studies that mostly report positive associations between mystical-type experiences and improvements in well-being. Other acute factors, such as psychological insights and emotional breakthroughs, may be similarly or even more closely associated with positive changes.

The acute, or subjective, experience is presumed to be completely absent in trip-free psychedelics. As the UC Davis study shows, there will be neuroplastic effects, but the administration could be as simple as getting a prescription. By eliminating the potentially overwhelming perceptual alterations, these substances increase the accessibility of psychedelic therapy for a wider range of patients.

Does the UC Davis study argue that these experiences, the epiphenomena of psychedelics, don’t matter? No; without human studies where these trip-free molecules are used at scale, there is no good answer to give yet. Researchers may discover that the acute experience is the driving force behind therapeutic benefits, or simply that it works in tandem with the neuroplastic effects. They may also find it is totally irrelevant, or even interfere with the physiological effects, dampening long-term outcomes. 

If psychedelics that only promote neuroplasticity, without acute hallucinogenic effects, can be developed, administration costs may decrease significantly. As I covered in my previous column, the costs of psychedelic-assisted therapy may be too steep to be used broadly. And recent events show that building non-FDA-regulated industries around retreats is still very challenging.

On the other hand, are we foregoing the mystical and introspective parts of psychedelics that many consider one of the most meaningful moments of their lives? Researchers David Yaden, Brian Earp, and Roland Griffiths are clear about their reason for prioritizing the subjective psychedelic experience. They argue that “such nonsubjective psychedelics should be reserved for those special cases in which the subjective effects of psychedelics are specifically contraindicated, whereas classic psychedelics that affect subjective experience should be considered the default and standard of care.”

Withholding these meaningful experiences may not be the only answer. But if these novel psychedelic-like compounds find their way through the arduous clinical trial process, they may be the most easily available, and impact the greatest number of lives.

Featured image: Made by Blossom using Midjourney

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