5-HT2A receptor

Gene

The 5-HT_2A receptors is coded by the HTR2A gene. In humans the gene is located on chromosome 13. The gene has previously been called just HTR2 until the description of two related genes HTR2B and HTR2C. Several interesting polymorphisms have been identified for HTR2A: A-1438G (rs6311), C102T (rs6313), and His452Tyr (rs6314). Many more polymorphisms exist for the gene. A 2006 paper listed 255.

Probable role in fibromyalgia as the T102C polymorphisms of the gene 5HT2A were common in fibromyalgia patients.

Human HTR2A gene is thought to consist of 3 introns and 4 exons and to overlap with human gene HTR2A-AS1 which consists of 18 exons. There are over 200 organisms that have orthologs with the human HTR2A. Currently, the best documented orthologs for HTR2A gene are the mouse, and zebrafish. There are 8 paralogs for the HTR2A gene. The HTR2A gene is known to interact and activate G-protein genes such as GNA14, GNAI1, GNAI3, GNAQ, and GNAZ. These interactions are critical for cell signaling and homeostasis in many organisms.

In human brain tissue, regulation of HTR2A varies depending on the region: frontal cortex, amygdala, thalamus, brain stem and cerebellum. In a paper from 2016, they found that HTR2A undergoes a variety of different splicing events, including utilization of alternative splice acceptor sites, exon skipping, rare exon usage, and intron retention.

Transcriptional regulation

There are a few mechanisms of regulation for HTR2A gene such regulated by DNA methylation at particular transcript binding sites. Another mechanism for the correct regulation of gene expression is achieved through alternative splicing. 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. These mRNA variants result in different isoforms which may have antagonistic functions or differential expression patterns, yielding plasticity and adaptability to the cells. One study found that the common genetic variant rs6311 regulates expression of HTR2A transcripts containing the extended 5' UTR.

Tissue distribution

5-HT_2A is expressed widely throughout the central nervous system (CNS). It is expressed near most of the serotonergic terminal rich areas, including neocortex (mainly prefrontal, parietal, and somatosensory cortex) and the olfactory tubercle . 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 by enhancing glutamate release followed by a complex range of interactions with the 5-HT_1A, GABA_A, adenosine A₁, AMPA, mGluR_2/3, mGlu5, and OX₂ receptors. In the rat cerebellum, the protein has also been found in the Golgi cells of the granular layer, and in the Purkinje cells.

In the periphery, it is highly expressed in platelets and many cell types of the cardiovascular system, in fibroblasts, and in neurons of the peripheral nervous system. Additionally, 5-HT_2A mRNA expression has been observed in human monocytes. Whole-body distribution of the 5-HT_2A/2C receptor agonist, [11C]Cimbi-36 show uptake in several internal organs and brown adipose tissue (BAT), but it is not clear if this represents specific 5-HT_2A receptor binding.

Structure

The 5-HT_2A receptor is a member of the class A (rhodopsin-like) G protein-coupled receptor (GPCR) family, characterized by seven transmembrane α-helices connected by extracellular and intracellular loops. Its ligand-binding pocket is composed of two adjacent subpockets: the orthosteric binding pocket (OBP) and an extended binding pocket (EBP), with a unique side-extended cavity near the orthosteric site that distinguishes it from related receptors. Ligands are anchored primarily through a conserved aspartate residue (D155^3.32) that interacts with their charged amine groups, while additional interactions involve hydrophobic contacts and hydrogen bonds with residues in both the OBP and EBP. Structural studies reveal that the receptor undergoes significant conformational changes upon activation, particularly in transmembrane helices 3 and 6, which facilitate G protein coupling and signal transduction. The extracellular ligand-binding pocket is closed by a flexible "lid," and the intracellular region includes a short helix (H8) stabilized by π-stacking interactions, both of which contribute to the receptor's dynamic conformational landscape. These structural features underlie the receptor's ability to recognize diverse ligands and mediate complex signaling behaviors.

The cryo-EM structures of the serotonin 5-HT_2A receptor with a variety of serotonin 5-HT_2A receptor agonists, including the tryptamines serotonin (neurotransmitter and endogenous agonist), psilocin (psychedelic), and dimethyltryptamine (DMT) (psychedelic), the lysergamides LSD (psychedelic) and 2-bromo-LSD (BOL-148) (non-hallucinogenic), and the phenethylamines mescaline (psychedelic) and RS130-180 (β-arrestin-biased agonist with unknown hallucinogenic potential), have been solved and published by Bryan Roth and colleagues.

Function

The 5-HT_2A receptor is a subtype of serotonin receptor that plays a critical role in the central nervous system, particularly in regions involved in cognition, learning, and memory. It is highly expressed in the cerebral cortex, especially in layer V pyramidal neurons and certain interneurons, where it modulates thalamocortical information processing and may influence gamma oscillations, which are important for sensory integration and perception. Functionally, the 5-HT_2A receptor is a G protein-coupled receptor (GPCR) that primarily signals through the phospholipase C (PLC) pathway, leading to the production of inositol triphosphate (IP3) and diacylglycerol, but it can also activate other signaling cascades such as arachidonic acid and 2-arachidonylglycerol pathways. Notably, the receptor exhibits "functional selectivity," meaning different ligands can differentially activate these signaling pathways, which is relevant for the distinct effects of hallucinogens, antipsychotics, and antidepressants that target the receptor. Activation of the 5-HT2A receptor by agonists is associated with enhanced cognition and hallucinogenic effects, while antagonists have antipsychotic and antidepressant properties. Dysregulation of 5-HT_2A receptor function has been implicated in psychiatric disorders such as depression, schizophrenia, and drug addiction. Additionally, the receptor undergoes unique regulatory processes, including desensitization and internalization that are partly independent of β-arrestin, further distinguishing it from other GPCRs and influencing its response to long-term pharmacological modulation.

Signaling cascade

The 5-HT_2A receptor is known primarily to couple to the Gα_q signal transduction pathway. Upon receptor stimulation with agonist, Gα_q and β-γ subunits dissociate to initiate downstream effector pathways. Gα_q stimulates phospholipase C (PLC) activity, which subsequently promotes the release of diacylglycerol (DAG) and inositol triphosphate (IP3), which in turn stimulate protein kinase C (PKC) activity and Ca²⁺ release.

Effects

Physiological processes mediated by the receptor include:

• CNS: neuronal excitation, hallucinations, out-of-body experiences, and fear. Primarily responsible for the psychedelic effects associated with 5-HT_2A receptor agonists such as LSD, DMT, etc.
• Activation of the 5-HT_2A receptor with 2,5-dimethoxy-4-iodoamphetamine (DOI) produces potent anti-inflammatory effects in several tissues including cardiovascular and gut. Other 5-HT_2A agonists like LSD also have potent anti-inflammatory effects against TNF-alpha-induced inflammation.
• Activation of the 5-HT_2A receptor in hypothalamus causes increases in hormonal levels of oxytocin, prolactin, ACTH, corticosterone, and renin.
• Role in memory and learning.
• Role in arthralgia.
• Role in Alzheimer's disease.
• Smooth muscle contraction in the gut.
• Probable role in sleep paralysis.
• Probable role in aging.

Ligands

Agonists

Activation of the 5-HT_2A receptor is necessary for the effects of the "classic" psychedelics like LSD, psilocin and mescaline, which act as full or partial agonists at this receptor, and represent the three main classes of 5-HT_2A agonists, the ergolines, tryptamines and phenethylamines, respectively. A very large family of derivatives from these three classes has been developed, and their structure-activity relationships have been extensively researched. Agonists acting at 5-HT_2A receptors located on the apical dendrites of pyramidal cells within regions of the prefrontal cortex are believed to mediate hallucinogenic activity. Some findings reveal that psychoactive effects of classic psychedelics are mediated by the receptor heterodimer 5-HT_2A–mGlu2 and not by monomeric 5-HT_2A receptors. However, newer research suggests that 5HT_2A and mGlu2 receptors do not physically associate with each other, so the former findings have questionable relevance. Agonists enhance dopamine in PFC, enhance memory and play an active role in attention and learning.

Serotonin 5-HT_2A receptor agonists include serotonergic psychedelics and non-hallucinogenic agents. Psychedelics have widely been encountered as recreational drug or drugs of misuse, with potential clinical consequences such as overdose, hospitalization, bad trips and worsened mental health, and rare adverse effects such as seizures, psychosis, and hallucinogen persisting perception disorder (HPPD). On the other hand, psychedelics and non-hallucinogenic serotonin 5-HT_2A receptor agonists are under development as novel treatments for psychiatric disorders like depression, anxiety, and addiction as well as other conditions like cluster headaches. Both psychedelics and non-hallucinogenic serotonin 5-HT_2A receptor agonists are claimed to act as psychoplastogens and this might be involved in their therapeutic effects.

Anti-inflammatory effects

Various serotonergic psychedelics, acting as serotonin 5-HT_2A receptor agonists, have been found to be highly potent and efficacious anti-inflammatory and immunomodulatory agents in preclinical research (i.e., animal and in-vitro studies). In contrast to corticosteroids however, psychedelics with anti-inflammatory effects do not appear to suppress the immune system. Some psychedelics have been found to be far more potent in their anti-inflammatory effects than in their psychedelic effects. For instance, (R)-DOI is 30- to >50-fold more potent in producing anti-inflammatory effects than in producing psychedelic-like behavioral effects in animal research. Psilocin, the active form of psilocybin, has similar anti-inflammatory potency as (R)-DOI.

The potencies of psychedelics and other serotonin 5-HT_2A receptor agonists as anti-inflammatory drugs vary, with 2C-I, DOIB, 2C-B, 4-HO-DiPT, DOI, 2,5-DMA, DOET, DOM, psilocin, and 2C-H being highly potent and fully efficacious anti-inflammatories; TMA-2, 2C-B-Fly, TCB-2, ETH-LAD, LSD, and 2C-T-33 being partially efficacious anti-inflammatories; and lisuride, 1-methylpsilocin, 5-MeO-DMT, and DMT having negligible efficacy. Although DMT and 5-MeO-DMT lack appreciable anti-inflammatory efficacy via the serotonin 5-HT_2A receptor, both have been reported to modulate inflammatory responses in human dendritic cells via the sigma σ₁ receptor. Both non-hallucinogenic agents with full anti-inflammatory effects, such as 2,5-DMA, and non-anti-inflammatory agents with full psychedelic effects, such as DOTFM, are known. Hence, the psychedelic and anti-inflammatory effects of serotonin 5-HT_2A receptor agonists appear to be fully dissociable. These effects appear to be mediated by different intracellular signaling pathways, although the exact pathways are unclear.

Serotonin 5-HT_2A receptor agonists with anti-inflammatory effects but reduced psychedelic effects, such as 2C-iBu (ELE-02), are under development for the potential treatment of inflammatory conditions. They may also have applications in the treatment of neuroinflammation. The anti-inflammatory effects of psychedelics might be involved in the claimed effects of psychedelic microdosing. Relatedly, LSD microdosing is being studied in the treatment of Alzheimer's disease specifically for its anti-inflammatory effects.

Full agonists

• 25B-NBOMe – also known as Cimbi-36; used as a PET imaging tool for visualizing the 5-HT_2A receptor
• 25I-NBOH and its 2-methoxy-analog 25I-NBOMe
• BMB-202 – highly selective
• ¹⁸F FECIMBI-36 – radiolabelled agonist ligand for mapping 5-HT_2A / 5-HT_2C receptor distribution
• 5-Methoxytryptamine – full agonist to several serotonin receptors.
• O-4310 – 5-HT_2A selective, claimed to have 100× selectivity over 5-HT_2C and be inactive at 5-HT_2B
• PHA-57378 – dual 5-HT_2A / 5-HT_2C agonist, anxiolytic effects in animal studies.
• TCB-2

Partial agonists

• 25C-NBOMe
• 25CN-NBOH – 100× selectivity for 5-HT_2A over 5-HT_2C, 46× selectivity over 5-HT_2B.
• 3-Carboxy indole PB-22 (1-pentyl-indole-3-carboxylic acid) – a metabolite of the synthetic cannabinoid PB-22, partial agonist at 5-HT_2A
• BMB-201 – non-hallucinogenic-like in animals
• Bromo-DragonFLY
• DMBMPP – a structurally constrained derivative of 25B-NBOMe, which acts as a potent partial agonist with 124× selectivity for 5-HT_2A over 5-HT_2C, making it the most selective agonist ligand identified to date.
• (R)-DOI – traditionally the most common 5-HT_2A reference agonist used in research
• Efavirenz – an antiretroviral drug, produces psychiatric side effects thought to be mediated by 5-HT_2A.
• IHCH-7113 – 5-HT_2A agonist derived by simplification of the 5-HT_2A antagonist antipsychotic lumateperone.
• Lisuride – an antiparkinson dopamine agonist of the ergoline class, that is also a dual 5-HT_2A / 5-HT_2C agonist and 5-HT_2B antagonist.
• Mefloquine – an antimalarial drug, also produces psychiatric side effects which may be mediated through 5-HT_2A and/or 5-HT_2C receptors.
• Methysergide – a congener of methylergonovine, used in treatment of migraine blocks 5-HT_2A and 5-HT_2C receptors, but sometimes acts as partial agonist, in some preparations.
• Piperidine derivatives such as OSU-6162, which acts as a partial agonist at both 5-HT_2A and dopamine D₂ receptors, and Z3517967757.
• Quipazine – 5-HT_2A agonist but also potent 5-HT₃ agonist.
• SN-22 – partial agonist at all three 5-HT₂ subtypes
• Some benzazepines and similar compounds related to lorcaserin such as SCHEMBL5334361 are potent 5-HT_2A agonists as well as showing action at 5-HT_2C.
• Substituted tetrahydro-β-carboline
• Tetrahydropyridine derivatives such as (R)-69, Z4154032166 and WXVL_BT0793LQ2118.
• Zalsupindole (DLX-001; AAZ-A-154) – non-hallucinogenic but retains antidepressant effects in animals.

Selective agonists

• 25CN-NBOH
• BMB-202
• DMBMPP
• DOI-NBOMe
• LPH-5
• LPH-48
• Lysergine
• O-4310
• TGF-8027

Peripherally selective agonists

One effect of 5-HT_2A receptor activation is a reduction in intraocular pressure, and so 5-HT_2A agonists can be useful for the treatment of glaucoma. 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. Animal studies with this compound showed it to be free of hallucinogenic effects at doses up to 30 mg/kg, although several of its more lipophilic analogues did produce the head-twitch response known to be characteristic of hallucinogenic effects in rodents. IHCH-8110 is a peripherally selective serotonin 5-HT_2A receptor agonist with beneficial effects against colorectal cancer in preclinical research.

Antagonists

Serotonin 5-HT_2A receptor antagonists, including many atypical antipsychotics, more selective agents like pimavanserin, and certain antidepressants and hypnotics like trazodone, mirtazapine, tricyclic antidepressants, and hydroxyzine, are used in the treatment of psychiatric disorders and other conditions such as depression, anxiety, psychosis, and insomnia. Ketanserin, a dual serotonin 5-HT_2A receptor antagonist and α₁-adrenergic receptor antagonist, is used as an antihypertensive agent. The non-selective serotonin 5-HT_2A receptor antagonist cyproheptadine is frequently used off-label to treat serotonin syndrome, albeit based on limited clinical evidence. Serotonin 5-HT_2A receptor antagonists like ketanserin have been used as psychedelic antidotes or "trip killers" to manage the hallucinogenic effects of serotonergic psychedelics.

List of antagonists

• 2-Alkyl-4-aryl-tetrahydro-pyrimido-azepines – subtype selective antagonists (35 g: 60-fold).
• 5-MeO-NBpBrT
• AMDA and related derivatives – family of selective 5-HT_2A antagonists.
• Atypical antipsychotics – e.g., quetiapine, and asenapine are relatively potent antagonists of 5-HT_2A
• Brexpiprazole – an atypical antipsychotic, is a potent antagonist at 5-HT_2A receptors (K_i = 0.47 nM in humans).
• Cariprazine
• Cyclobenzaprine – a strong antagonist of both 5-HT_2A and 5-HT_2C receptors
• Cyproheptadine
• Ergot alkaloids are mostly nonspecific 5-HT receptor antagonists, but a few ergot derivatives such as metergoline and nicergoline bind preferentially to members of the 5-HT₂ receptor family.
• Hydroxyzine (Atarax) (minor effect)
• Ketanserin – The discovery of ketanserin was a landmark in the pharmacology of 5-HT₂ receptors. Ketanserin, though capable of blocking 5-HT induced platelet adhesion, however does not mediate its well-known antihypertensive action through 5-HT₂ receptor family, but through its high affinity for alpha₁ adrenergic receptors. It also has high affinity for H₁ histaminergic receptors equal to that at 5-HT_2A receptors. Compounds chemically related to ketanserin such as ritanserin are more selective 5-HT_2A receptor antagonists with low affinity for alpha-adrenergic receptors. However, ritanserin, like most other 5-HT_2A receptor antagonists, also potently inhibits 5-HT_2C receptors.
• Lumateperone
• LY-367,265 – dual 5-HT_2A antagonist / SSRI with antidepressant effects
• Nantenine
• Nefazodone – blocks post-synaptic 5-HT_2A receptors, and to a lesser extent inhibits pre-synaptic serotonin and norepinephrine reuptake.
• Niaprazine
• Opipramol – atypical antidepressant
• Pizotifen – a non-selective antagonist.
• Trazodone – a potent 5-HT_2A antagonist, as well as an antagonist on other serotonin receptors.
• Tetracyclic antidepressants – mianserin, mirtazapine, maprotiline
• Tricyclic antidepressants (TCAs) – e.g., amitriptyline, nortriptyline, amoxapine, clomipramine, doxepin, maprotiline, imipramine, iprindole
• Typical antipsychotics – e.g., haloperidol and chlorpromazine (minor)
• Volinanserin (MDL100907, M100907) – the most potent 5-HT_2A antagonist; underwent a few clinical trials but was ultimately never marketed.

Peripherally selective antagonists

• BW-501C67
• Irindalone – partial
• Sarpogrelate
• Xylamidine

Antagonists and cardiovascular disease

Increased 5-HT_2A expression is observed in patients with coronary thrombosis, and the receptor has been associated with processes that influence atherosclerosis. As the receptor is present in coronary arteries and capable of mediating vasoconstriction, 5-HT_2A has also been linked to coronary artery spasms. 5-HT antagonism, therefore, has potential in the prevention of cardiovascular disease, however, no studies have been published so far.

Inverse agonists

• AC-90179 – potent and selective inverse agonist at 5-HT_2A, also 5-HT_2C antagonist.
• Atypical antipsychotics – clozapine, iloperidone, olanzapine, paliperidone, risperidone
• Eplivanserin (Sanofi Aventis) – sleeping pill that reached phase II trials (but for which the application for approval was withdrawn), acts as a selective 5-HT_2A inverse agonist.
• Nelotanserin (APD-125) – selective 5-HT_2A inverse agonist developed by Arena Pharmaceuticals for the treatment of insomnia. APD-125 was shown to be effective and well tolerated in clinical trials.
• Pimavanserin (ACP-103) – more selective than AC-90179, orally active, antipsychotic in vivo, now FDA approved for the treatment of hallucinations and delusions associated with Parkinson's disease.

Positive allosteric modulators

Positive allosteric modulators of the serotonin 5-HT_2A receptor have been identified. These include CTW0404 and CTW0419. They selectively potentiated the serotonin 5-HT_2A receptor without affecting the serotonin 5-HT_2B and 5-HT_2C receptors. Unlike serotonin 5-HT_2A 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 psychedelic effects. Instead, they blunted the (R)-DOI-induced head-twitch response. The (R)-enantiomer of glaucine has also been reported to be a serotonin 5-HT_2A receptor positive allosteric modulator. A dual serotonin 5-HT_2C and 5-HT_2A receptor positive allosteric modulator is the oleamide analogue JPC0323. Another selective serotonin 5-HT_2A receptor positive allosteric modulator is AB0124.

Functional selectivity

5-HT_2A-receptor ligands may differentially activate the transductional pathways (see above). Studies evaluated the activation of two effectors, PLC and PLA2, by means of their second messengers. Compounds displaying more pronounced functional selectivity are 2,5-DMA and 2C-N. The former induces IP accumulation without activating the PLA2 mediated response, while the latter elicits AA release without activating the PLC mediated response.

Recent research has suggested potential signaling differences within the somatosensory cortex between 5-HT_2A agonists that produce headshakes in the mouse and those that do not, such as lisuride, as these agents are also non-hallucinogenic in humans despite being active 5-HT_2A agonists. One known example of differences in signal transduction is between the two 5-HT_2A agonists serotonin and DOI that involves differential recruitment of intracellular proteins called β-arrestins, more specifically arrestin beta 2. Cyclopropylmethanamine derivatives such as (−)-19 have also been shown to act as 5-HT_2A/2C agonists with functional selectivity for Gq-mediated signaling compared with β-arrestin recruitment.

Serotonin-elevating drugs

Besides direct serotonin 5-HT_2A receptor agonists, many drugs elevate serotonin levels and indirectly activate serotonin 5-HT_2A receptors. Examples include antidepressants and anxiolytics such as selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and serotonin precursors like tryptophan and 5-hydroxytryptophan (5-HTP). In addition, serotonin releasing agents (SRAs), including appetite suppressants like fenfluramine and chlorphentermine and entactogens like MDMA, elevate serotonin levels and indirectly activate serotonin 5-HT_2A receptors similarly. Serotonin 5-HT_2A receptor activation may be involved in the therapeutic effects of serotonin-elevating medications and appears to be importantly involved in the subjective effects of SRAs like MDMA. Serotonin-elevating drugs can cause serotonin syndrome under certain circumstances, for instance in overdose or with combination of multiple serotonergic drugs, and the serotonin 5-HT_2A receptor appears to be a key serotonin receptor in mediating this syndrome.

Methods to analyse the receptor

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

Neuroimaging

The 5-HT_2A receptors may be imaged with PET-scanners using the fluorine-18-altanserin, MDL 100,907 or [¹¹C]Cimbi-36 radioligands that binds to the neuroreceptor, e.g., one study reported a reduced binding of altanserin particularly in the hippocampus in patients with major depressive disorder.

Altanserin uptake decreases with age reflecting a loss of specific 5-HT_2A receptors with age.

Other

Western blot with an affinity-purified antibody and examination of 5-HT_2A receptor protein samples by electrophoresis has been described. Immunohistochemical staining of 5-HT_2A receptors is also possible.

Clinical significance

Associations with psychiatric disorders

Several studies have seen links between the -1438G/A polymorphism and mood disorders, such as major depressive disorder and a strong link with an odds ratio of 1.3 has been found between the T102C polymorphism and schizophrenia.

The T102C polymorphism has also been studied in relation to suicide attempts, with a study finding excess of the C/C genotype among the suicide attempters. A number of other studies were devoted to finding an association of the gene with schizophrenia, with diverging results.

These individual studies may, however, not give a full picture: A review from 2007 looking at the effect of different SNPs reported in separate studies stated that "genetic association studies [of HTR2A gene variants with psychiatric disorders] report conflicting and generally negative results" with no involvement, small or a not replicated role for the genetic variant of the gene.

Polymorphisms in the promoter gene coding Early growth response 3 (EGR3) are associated with schizophrenia. Studies have demonstrated a relationship between EGR3 and HTR2A, and schizophrenia-like behaviors in transgenic animals. Exactly how these results translate over to further biopsychological understanding of schizophrenia is still widely debated. There is some evidence that dysfunction of HTR2A can impact pharmacological interventions.

Several studies have assessed a relationship between 5-hydroxytryptamine (serotonin) 2A receptor (5-HTR2A) gene polymorphisms with an increased risk of suicidal behavior. One study revealed that T102C polymorphism is associated with suicidal behavior but other studies failed to replicate these findings and found no association between polymorphism and suicidal behavior.

Treatment response

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

Associations with substance abuse

Polymorphisms in the 5-HT_2A receptor coding gene HTR2A (rs6313 and s6311) have been shown to have conflicting associations with alcohol misuse. For example, A polymorphism in the 5-HT_2A receptor coding gene HTR2A (rs6313) was reported to predict lower positive alcohol expectancy, higher refusal self-efficacy, and lower alcohol misuse in a sample of 120 young adults. However, this polymorphism did not moderate the linkages between impulsivity, cognition, and alcohol misuse. There are conflicting results as other studies have found associations between T102C polymorphisms alcohol misuse.

Drug impact on gene expression

There is some evidence that methylation patterns may contribute to relapse behaviors in people who use stimulants. In mice, psychotropic drugs such as DOI, LSD, DOM, and DOB which produced differing transcriptional patterns among several different brain regions.