Cellular Receptors and Their Role in the Psychedelic Effect

Research is revealing that the psychedelic effect is due to much more than 5-HT2A activation.

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Corpora non agunt nisi fixate.

[Substances do not act unless bound.]

–Paul Ehrlich1

Anyone who reads about how psychedelic drugs work comes across discussions about receptors. The serotonin receptors, particularly 5-HT2A, get a lot of attention. This is because many psychedelic drugs are derivatives or analogs of the endogenous neurotransmitter serotonin, which uses those receptors. But, there’s much more to know about receptors. Here’s a brief overview of how they work, the effects they have, and which ones experts currently think are involved in the effects of psychedelics.

What Are Receptors?

One definition of a receptor is,2

A cellular macromolecule, or an assembly of macromolecules, that is concerned directly and specifically in chemical signaling between and within cells.

To put it another way, receptors are cellular proteins that mediate the activity of molecules.3 They are found inside cells and spanning the cell membrane. The different types of receptors include membrane receptors like G protein-coupled receptors (GPCRs), ion channels, and receptors that activate enzymes.

How Do Receptors Work?

Although receptors are present at a high density on cells, they occupy only a tiny fraction of the cell’s surface area.4 Because of this, signals from receptors must be amplified to a sufficient intensity to elicit the effect. A signaling cascade is a series of events that amplify the signal and disseminates it quickly throughout the cell. This mechanism is also known as signal transduction.

Understanding how receptors work requires another definition. Substances that bind to receptors are called ligands. Simply stated, a ligand is a molecule that binds to a receptor and causes a biological response.

Now back to the signaling cascade. The cascade initiates when a ligand binds to a binding site (aka the recognition site) on the receptor. The binding triggers the activation of enzymes (often protein kinases). These enzymes, in turn, can have a variety of actions, including stimulating the creation of activators for other enzymes, changing protein configuration, and opening and closing ion channels. The cascade reaction happens until it is modulated or deactivated, often through feedback loops. As a result, the binding of a single ligand is translated into tens, possibly millions of activations that amplify the signal.

Modes of Receptor Interaction

Ligands can interact with receptors in several ways.3 Characterization of receptor/ligand interactions include aspects such as the strength of the attraction between the ligand and receptor (affinity), the relationship between the dose of the ligand and the magnitude of the effect (potency), and the degree of the response (efficacy). Here is an overview of a few types of receptor interactions.2

Agonists

An agonist is,

A ligand that binds to a receptor and alters the receptor state resulting in a biological response.

An agonist binds to a receptor like the endogenous compound does, but the effects may be quite different. For example, psilocin binding to the 5-HT2A receptor causes different effects than when serotonin binds to it. Partial agonists, as the name implies, have partial efficacy at a given receptor. Inverse agonists can be thought of as modified antagonists (see below). They block the receptor but also produce a negative response.

Antagonists

An antagonist is a compound that reduces the effects of an agonist by blocking the recognition site. It does not cause a conformational change in the protein as the ligand would. The chemical ketanserin is an example of an antagonist of the 5-HT2A receptor. It is a cardiovascular drug and is also used in receptor binding assays to study how the receptor works.

Allosteric Modulators

These compounds increase or decrease the action of an agonist or antagonist. They accomplish this by binding to an area other than where an endogenous agonist binds. Allosteric ligands are particularly useful for designing drugs that target GPCRs.5 Several serotonin receptor subtypes, including 5-HT2A, belong to the GPCR family.

Receptors Involved in the Psychedelic Effect

In terms of the serotonin receptors, studies have shown that activation of the 5-HT2A receptor by an agonist or partial agonist causes the psychedelic effect.6,7 Psychedelics researcher Dr. David Nichols theorizes that the 5-HT2C receptor may also have a role. In his landmark 2016 paper titled Psychedelics, he says,8

All known psychedelics are agonists at both the 5HT2A and 5-HT2C receptors…higher doses of particular psychedelics may lead to activation of the 5-HT2C receptor, which often functionally opposes the effects of 5-HT2A receptor activation.

In addition to 5-HT2A, the psychedelic compounds psilocin and 5-MeO-DMT have a high affinity for 5-HT1A.9,10 LSD activates the dopamine D2 receptor11 but is also a full agonist at 5-HT1A.12,13

David Nichols wrote in his 2004 paper titled Hallucinogens:14

Although the widespread consensus is that the activation of the 5-HT2A receptor is the essential pharmacological component in the actions of hallucinogens, it is still possible that interactions with other CNS receptors may modulate the overall psychopharmacology.

A Study Examining Several Psychedelic Compounds at Receptors

A 2010 paper published in PloS ONE analyzed the binding affinity data for 35 psychedelic drugs (primarily phenylalkylamines) at 51 receptors, transporters, and ion channels.15 The compounds included ones that are naturally occurring as well as synthetics.

The main observation from the data was that psychedelic drugs are not as selective as may be generally believed in the scientific community. The author Ray stated,

…psychedelics interact with a large number of receptors (forty-two out of the forty-nine sites at which most of the drugs were assayed).

In addition, the data indicated that psychedelics,

…exhibit diverse patterns of receptor interaction. Different drugs emphasize different classes of serotonin receptors.

For example, the author made these observations from the data (note: “hit” means inducing >50% inhibition in binding assays):

  • “5-HT2B is the best hit for thirteen drugs.”
  • “5-HT1A is the best hit for nine drugs.”
  • “Five of the top six psychedelic receptors are 5-HT1 and 5-HT2

The author summed up the findings in the study by saying,

This diversity of receptor interaction may underlie the qualitative diversity of these drugs. It should be possible to use this diverse set of drugs as probes into the roles played by the various receptor systems in the human mind.

Continuing Research on Psychedelic Receptors

Scientific research is slowly revealing the complex interplay between psychedelic compounds and receptors. Indeed, the work by Ray casts a wide net and provides some intriguing observations. His work serves as a springboard for studies to understand more about the pharmacology of psychedelics at a variety of receptors. Also, consider that multiple active compounds from naturally occurring sources set the stage for the entourage effect playing a critical role in making formulations.

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