Spend enough time in the psychedelic medicine space — as either an investor or advocate or enthusiast — and you’ll inevitably become familiar with terms like the 5HT-2A receptor. But what exactly is it? Why is it so important?
Guest science writer Elisabetta Fato takes a closer look at the 5HT-2A receptor.
Psychedelics don’t work solo
When thinking of psychedelics like LSD, psilocybin, MDMA or DMT, we tend to wonder how such tiny molecules can have such intense and often bizarre effects on our minds.
The answer, science is increasingly suggesting, resides as much in our bodies as in the actual substances. What would psychedelics be able to accomplish without their signalling mediators, their antennae, or, in more technical terms, their receptors?
So let’s explore the central features of 5HT-2A receptors, the principal targets of most hallucinogens.
Psychedelic physiology 101: an introduction
Psychedelics are thought to produce their hallucinogenic and anti-depressant effects through the receptors, or “nests”, embedded in our organism. But how?
Yet before getting starting with the how, let’s take a moment with the what. Here are some introductory concepts and terms to help get us started:
- A receptor is a protein on the cell surface that is bound by signalling molecules, such as neurotransmitters or drugs. Excitatory receptorson brain cells or neurons allow them to transmit an electrical signal, while inhibitory receptors block it.
- “Ligand” is a synonym for “signalling molecule”; they can bind to receptors in different ways.
- High and low-affinity receptors: the first is a receptor having a great ability to bind to a certain ligand, while the second does the opposite.
- Serotonin, an example of ligand. One of the most important neurotransmitters found in the brain and the gut. It is involved in mood, learning, memory, vascular and a wide variety of other physiological processes.
- Serotonergic: a receptor bound by serotonin or a ligand other than serotonin that binds to serotonin receptors by mimicking serotonin’s structure.
- Agonist: a ligand that activates the receptor causing a full response.
- Partial agonist: a ligand that partially activates the receptor and leads to a lower maximal response.
“Psychedelics’ Antennae”: Where are 5HT-2A receptors found and what’s their mechanism of action?
5HT-2A are the major excitatory receptors for serotonin (5HT). 5HT receptors are a subset of G-protein coupled receptors (GPCRs), which, as the name says, are coupled to a type of protein called “G-protein. Once the ligand binds to the receptor, the G-protein changes its structure, eventually leading to a cellular response. (figure g).
Figure g. A model describing the mechanism at the base of GPCR signalling, shared by all GPCRs
Located in areas of the brain that play a prominent role in emotions, memory, and perception — including the amygdala, the prefrontal and the anterior cingulate cortices (figure c) — psychedelics-induced hallucinogenic effects are thought to originate mainly from the interaction of the ligand (any serotonergic psychedelic) with the 5HT-2A receptors expressed on the pyramidal cells in layer V of the cortex.
Figure c. PET scan picturing the expression level of 5HT-2A receptors in different brain areas, with the highest detection in the cortex.
Activation of 5HT-2A triggers multiple cellular events, such as increased activation of the glutaminergic AMPA receptor and changes in the expression level of some proteins, which altogether result in neurogenesis, neuroplasticity and synaptogenesis, in the prefrontal cortex in particular. These developments are believed to underlie their antidepressant effects, as well as enhanced memory and learning.
Although most psychedelics act as full or partial agonists on various types of serotonin receptors, there is plenty of evidence that activation of the 5HT-2A isotype is the main mediator of psychedelics-induced hallucinogenic effects.
In one experiment, for example, when psilocybin was administered after blocking 5HT-2A receptors with an antagonist, none of the behavioural effects usually elicited by the drug was observed.
Moreover, in a different study, a very strong correlation was found between the interaction of psilocybin with the 5HT-2A receptors and the intensity of psilocybin-induced effects.
Environment is key in 5HT-2A receptor agonism
Both 5HT-2A and 5HT-1A are the main serotonin (5HT) receptors in the brain and seem to counterbalance each other’s effects through their opposing functions (figure n).
The inhibitory 5HT-1A has high affinity for serotonin and is involved in most daily activities; it acts by reducing anxiety and aggression.
Anti-depressants mostly target 5HT-1 type receptors to exploit these functions, but the adverse effects derived from their overall use include sexual impairment, weight gain, GI tract problems, not to mention the resistance to the treatment itself (“treatment-resistant depression”). Such downsides were not seen following administration of psychedelics.
Therefore, psychedelics-agonism at 5HT-2A receptors could represent an improvement in depression therapeutics.
5HT-2A receptors, on the other hand, need higher levels of serotonin to be activated (lower affinity). This occurs less frequently, usually in situations of stress, when 5HT levels rise to allow our body to cope with stress.
Figure n. The above diagram summarises the 2 main serotonergic pathways in the brain, mediated by 2 different receptors and performing opposite the functions (figure adapted from “Serotonin and brain function: a tale of two receptors” (Cahart-Harris, Nutt; 2017)
However, their action is not as easy and generalised as it might seem.
Agonistic binding to 5HT-2A by psychedelics, which mimic serotonin’s structure (figure j), can in fact result in a variety of different responses, which however depend on the surrounding environment.
Hence the fundamental role played by “set” and “setting” during a psychedelic experience. If taken in uncomfortable conditions (both in terms of the external environment and psychological state), psychedelics can trigger psychosis, anxiety and aggression, whereas comfortable settings favour positive, antidepressant effects, such as states of ego-loss, inner peace and mystical experiences.
Figure j. Molecular structure of serotonin, LSD and psilocybin (magic mushrooms). Their serotonin-like structure is what allows all serotonergic psychedelics to act as agonists on 5HT-2A receptors
5HT-2A outside the brain
Here we have gathered, in a nutshell, the major features characterising 5HT-2A receptors in the brain. However, they are expressed in various other locations in the body and mediate diverse effects, an example being GI tract smooth muscle contraction (when the receptors are bound by an agonist) or arthralgia (if blocked by an antagonist).
Conclusion
The scientific field of psychedelics research is a universe in continuous expansion, with the study of 5HT-2A receptors residing at its core. Only by understanding how our body allows these substances to work that we might be able to fully grasp its secrets.
Editor’s Note
This piece is part of a series produced by guest contributors to expand the voices on our site and in the greater conversation. While Microdose supports the education and exploration of these topics, the facts and opinions presented in this work are the author’s alone.
