What Receptors Do Psychedelics Affect? A Pharmacological Deep Dive

October 11, 2025 •

4 min read

Over 80% of clinical trial patients with advanced-stage cancer reported reduced anxiety and depression lasting over six months after a single dose of psilocybin, pointing to the profound and long-lasting neurological effects of these substances. A deep understanding of what receptors do psychedelics affect is crucial to unlock their therapeutic potential and distinguish them from other compounds.

Quick Summary

Psychedelics primarily agonize the 5-HT2A serotonin receptor but also interact with other serotonin subtypes, dopamine, and sigma-1 receptors. This complex multi-receptor action drives profound changes in consciousness and promotes long-term neuroplasticity.

Key Points

Primary Target: Serotonin 2A (5-HT2A) Receptor: Classic psychedelics, such as LSD and psilocybin, exert their primary effects by acting as agonists at the 5-HT2A receptor, which is abundant in the prefrontal cortex.
Intracellular vs. Extracellular Activation: Unlike endogenous serotonin, some psychedelics like DMT can cross cell membranes to activate 5-HT2A receptors inside neurons, a mechanism linked to promoting neuroplasticity.
Multi-Receptor Interactions (Polypharmacology): Beyond 5-HT2A, psychedelics engage a variety of other receptors, including other serotonin subtypes (5-HT1A, 5-HT2C), dopamine (D2), and sigma-1, which contribute to the drugs' diverse effects.
Impact on Neuroplasticity: The complex receptor activity induced by psychedelics promotes neuroplasticity, including increased synaptic density and dendritic growth, which may underpin the long-term therapeutic effects.
Disruption of the Default Mode Network (DMN): Psychedelics temporarily reduce communication within the DMN, a brain network associated with self-referential thought. This is linked to the experience of 'ego dissolution' and a sense of connectedness.
Distinction from Other Psychoactive Drugs: Atypical psychedelics like salvinorin A target kappa opioid receptors, while dissociatives like ketamine block NMDA glutamate receptors, showcasing different mechanisms from classic serotonergic psychedelics.

The central role of the 5-HT2A serotonin receptor

At the core of the psychedelic experience lies the serotonin 2A receptor, or 5-HT2A. This G protein-coupled receptor (GPCR) is located predominantly in the neocortex, an area of the brain vital for mood, cognition, and perception. When classic psychedelics like LSD and psilocybin enter the brain, they act as agonists, binding to and activating 5-HT2A receptors.

This activation is directly responsible for the hallmark hallucinogenic effects. By activating these receptors, psychedelics cause cortical neurons to fire in a more asynchronous and disorganized manner, which is thought to introduce 'noise' into the brain's system and alter perception. Furthermore, studies using antagonists (drugs that block receptors) show that blocking the 5-HT2A receptor prevents the subjective effects of psychedelics, confirming its essential role.

Beyond the cell surface: Intracellular activation

Recent research has added a new layer of complexity to the 5-HT2A story. Scientists have discovered that some psychedelics, particularly lipophilic compounds like DMT and psilocin, can pass through cell membranes to activate 5-HT2A receptors located inside neurons, specifically around the Golgi body. This contrasts with endogenous serotonin, which primarily acts on cell-surface receptors. The location of receptor activation seems to matter profoundly:

Intracellular activation: Binding to 5-HT2A receptors inside the cell appears to be critical for promoting neuroplasticity—the growth of new dendritic branches and spines on neurons.
Surface activation: While also contributing, surface receptor engagement may have different effects, and the discovery of this 'location bias' offers deeper insights into how psychedelics differ from other substances.

The psychedelic polypharmacology: More than just 5-HT2A

While 5-HT2A is the primary target for classic psychedelics, these compounds often engage in a more complex 'polypharmacology', interacting with many other receptors. This broader activity is believed to contribute to the diversity of psychedelic experiences and their potential therapeutic benefits.

Other serotonin receptors

Many psychedelics interact with additional serotonin receptor subtypes, including:

5-HT1A receptors: Evidence suggests these may modulate the subjective experience of psychedelics and play a potential role in their therapeutic outcomes for conditions like depression. Psilocin has a high affinity for both 5-HT1A and 5-HT2A.
5-HT2C receptors: These are also a target for many classic psychedelics and have been studied for their role in addiction and appetite regulation.

Dopamine and other systems

Several psychedelics and related compounds influence other neurotransmitter systems:

Dopamine: LSD shows high affinity for dopamine D2 receptors. MDMA, often classified as an entactogen but with some psychedelic properties, stimulates the release of serotonin, dopamine, and norepinephrine. This activity in dopamine pathways, particularly in the nucleus accumbens, can influence reward signaling, motivation, and mood.
Sigma-1 Receptor: The hallucinogen DMT acts as an agonist at the sigma-1 receptor, an intracellular protein involved in a wide range of physiological functions, including modulation of ion channels and memory.
Glutamate/NMDA: Dissociative drugs like ketamine and PCP act on the glutamate system by blocking N-methyl-D-aspartate (NMDA) receptors. Glutamate plays a major role in learning and memory.
Kappa Opioid Receptors: The atypical psychedelic salvia divinorum primarily acts on kappa opioid receptors.

Long-term effects and functional connectivity

The complex multi-receptor action of psychedelics ultimately drives profound changes at the systems level. One of the most significant effects is the temporary disruption of the default mode network (DMN), a collection of brain regions associated with introspection and self-referential thought. By disrupting the DMN, psychedelics may induce a more expansive state of consciousness, leading to experiences like ego dissolution and a sense of connectedness.

This acute neural disorganization is coupled with long-term neuroplastic changes. Studies have shown that psychedelics promote the growth and density of synaptic connections in the brain. This effect, often mediated by the intracellular activation of 5-HT2A and other pathways, is hypothesized to underlie the lasting therapeutic benefits observed in clinical research for conditions like depression and addiction. The increased neuroplasticity may enable the brain to break out of entrenched, maladaptive thought patterns associated with these disorders.

Comparison of psychedelic receptor activity


Psychedelic	Primary Receptor	Other Key Receptors	Key Neurochemical Systems	Notes
LSD	High affinity 5-HT2A agonist	Wide array of 5-HT subtypes, D2 dopamine, adrenergic receptors	Serotonin, Dopamine, Adrenergic	Potent, with a broad receptor profile.
Psilocybin (Psilocin)	High affinity 5-HT2A agonist	5-HT1A, 5-HT2C	Serotonin	Active compound (psilocin) has a high affinity for multiple 5-HT receptors.
DMT (Dimethyltryptamine)	High affinity 5-HT2A agonist	5-HT1A, Sigma-1 receptor	Serotonin, Sigma	Can activate intracellular 5-HT2A receptors.
Mescaline	5-HT2A	5-HT1A, 5-HT2C	Serotonin	Less studied compared to LSD and psilocybin.
MDMA	Primary Serotonin Releaser	Weakly activates 5-HT receptors, increases dopamine and norepinephrine	Serotonin, Dopamine, Norepinephrine	Differs from classic psychedelics, but has overlapping effects.
Salvinorin A	Kappa Opioid Receptor agonist	N/A	Kappa Opioid	Atypical psychedelic with a unique mechanism of action.

Conclusion: A multi-faceted pharmacological picture

The question of what receptors do psychedelics affect reveals a complex pharmacological landscape far beyond a single target. While the 5-HT2A receptor remains the central player for classic hallucinogenic effects, the interaction with other serotonin subtypes, dopamine receptors, and even the intracellular location of 5-HT2A, contributes to the full spectrum of their effects. The resulting multi-system modulation and enhanced neuroplasticity offer a compelling explanation for both the altered states of consciousness and the long-lasting therapeutic potential observed in clinical trials.

Continued research into this multifaceted mechanism is paving the way for more targeted and safer psychedelic-inspired medicines. By understanding the intricate interplay between different receptors, researchers can potentially design compounds that separate the therapeutic benefits from the intense subjective experiences, marking a new era for psychiatric medicine. For more information on receptor binding profiles, the NIH Psychoactive Drug Screening Program offers a comprehensive database.

NIH Psychoactive Drug Screening Program (PDSP)

Frequently Asked Questions

The primary receptor activated by classic psychedelics is the 5-HT2A receptor, a subtype of serotonin receptor located predominantly in the neocortex.

Yes, psychedelics have a complex pharmacology and interact with a broad array of other receptors. These include other serotonin subtypes like 5-HT1A and 5-HT2C, dopamine receptors, and the sigma-1 receptor.

The differing effects can be attributed to each compound's unique receptor binding profile, its potency, and whether it acts at intracellular or extracellular receptor sites. For example, LSD has a broader receptor profile than psilocybin, which may contribute to its distinct effects.

Activating intracellular 5-HT2A receptors, particularly by fat-soluble psychedelics like DMT, has been linked to the promotion of neuroplasticity (the growth of new synapses), which is thought to be key to the long-term therapeutic effects.

Psychedelics temporarily reduce the functional connectivity within the DMN, a brain network associated with self-referential thought. This disruption is believed to be the basis for experiences of ego dissolution and increased interconnectedness.

No. While classic psychedelics primarily target the 5-HT2A receptor, other hallucinogens have different mechanisms. For example, the dissociative drug ketamine blocks NMDA receptors, and salvia divinorum activates kappa opioid receptors.

Neuroplasticity is the brain's ability to reorganize itself by forming new neural connections. The binding of psychedelics to various receptors, particularly 5-HT2A, can trigger intracellular signaling cascades that promote this process, especially the growth of dendritic spines.