[8] This receptor was first noted for its importance as a target of serotonergic psychedelic drugs such as LSD and psilocybin mushrooms.

Downregulation of post-synaptic 5-HT2A receptor is an adaptive process provoked by chronic administration of selective serotonin reuptake inhibitors (SSRIs) and atypical antipsychotics.

Neither tolerance nor rebound is observed in humans with regard to the slow-wave sleep (SWS) promoting effects of 5-HT2A antagonists.

Upon receptor stimulation with agonist, Gαq and β-γ subunits dissociate to initiate downstream effector pathways.

[15] In the era before molecular cloning, when radioligand binding and displacement was the only major tool, spiperone and LSD were shown to label two different 5-HT receptors, and neither of them displaced morphine, leading to naming of the 5-HT1, 5-HT2 and 5-HT3 receptors, corresponding to high affinity sites from LSD, spiperone and morphine, respectively.

[18] It is expressed near most of the serotonergic terminal rich areas, including neocortex (mainly prefrontal, parietal, and somatosensory cortex) and the olfactory tubercle [citation needed].

Especially high concentrations of this receptor on the apical dendrites of pyramidal cells in layer V of the cortex may modulate cognitive processes, working memory, and attention[19][20][21] by enhancing glutamate release followed by a complex range of interactions with the 5-HT1A,[22] GABAA,[23] adenosine A1,[24] AMPA,[25] mGluR2/3,[26] mGlu5,[27] and OX2 receptors.

[48][49] Agonists acting at 5-HT2A receptors located on the apical dendrites of pyramidal cells within regions of the prefrontal cortex are believed to mediate hallucinogenic activity.

This has led to the development of compounds such as AL-34662 that are hoped to reduce pressure inside the eyes but without crossing the blood–brain barrier and producing hallucinogenic side effects.

[92] Increased 5-HT2A expression is observed in patients with coronary thrombosis, and the receptor has been associated with processes that influence atherosclerosis.

[115][116] Unlike serotonin 5-HT2A receptor agonists, they did not substitute for the serotonergic psychedelic (R)-DOI in drug discrimination tests and did not produce the head-twitch response, suggesting that they lack hallucinogenic effects.

[118][119] One known example of differences in signal transduction is between the two 5-HT2A agonists serotonin and DOI that involves differential recruitment of intracellular proteins called β-arrestins, more specifically arrestin beta 2.

[120][121] Cyclopropylmethanamine derivatives such as (−)-19 have also been shown to act as 5-HT2A/2C agonists with functional selectivity for Gq-mediated signaling compared with β-arrestin recruitment.

This is a co-transcriptional process, which allows the generation of multiple forms of mRNA transcript from a single coding unit and is emerging as an important control point for gene expression.

In this process, exons or introns can be either included or excluded from precursor-mRNA resulting in multiple mature mRNA variants.

[135] These mRNA variants result in different isoforms which may have antagonistic functions or differential expression patterns, yielding plasticity and adaptability to the cells.

[136] One study found that the common genetic variant rs6311 regulates expression of HTR2A transcripts containing the extended 5' UTR.

[146] Several studies have assessed a relationship between 5-hydroxytryptamine (serotonin) 2A receptor (5-HTR2A) gene polymorphisms with an increased risk of suicidal behavior.

[148] Genetics seems also to be associated to some extent with the amount of adverse events in treatment of major depression disorder.

[143] The receptor can be analysed by neuroimaging, radioligand, genetic analysis, measurements of ion flows, and other ways.