Serotonin 5-HT2A receptor agonist

A serotonin 5-HT_2A receptor agonist, or simply 5-HT_2A agonist, is a drug which acts as an agonist of the serotonin 5-HT_2A receptor.^[1][2] The serotonin 5-HT_2A receptor is one of 13 known human serotonin receptors.^[3] Serotonin 5-HT_2A receptor agonists can be divided into two main groups: (1) serotonergic psychedelics such as LSD, psilocybin, and mescaline; and (2) non-hallucinogenic serotonin 5-HT_2A receptor agonists such as lisuride, Ariadne, tabernanthalog, and zalsupindole, among others.^[1][4] Psychedelic and non-hallucinogenic serotonin 5-HT_2A receptor agonists can be reliably distinguished from each other in scientific research using the head-twitch response assay in animals.^[5][4][6]

Serotonin 5-HT2A receptor agonist
Drug class
Psilocybin, a well-known non-selective agonist of the serotonin 5-HT2A receptor and other serotonin receptors and a serotonergic psychedelic.
Class identifiers
Synonyms	5-HT2A agonist
Use	Hallucinogenic effects, treatment of psychiatric and other disorders
Mechanism of action	Serotonin 5-HT2A receptor agonism
Biological target	Serotonin 5-HT2A receptor
Chemical class	Tryptamines, phenethylamines, ergolines, lysergamides, others
Legal status
In Wikidata

Agonists of the serotonin 5-HT_2A receptor are generally not selective for this receptor and also interact with other serotonin receptors, such as the serotonin 5-HT_1A, 5-HT_2B, and/or 5-HT_2C receptors, among others.^[7][8] However, highly selective serotonin 5-HT_2A receptor agonists, such as TGF-8027, have also been developed.^[9] In addition to degree of selectivity for the serotonin 5-HT_2A receptor, the serotonin 5-HT_2A receptor activates a variety of different downstream signaling pathways, such as G protein and β-arrestin cascades, and serotonin 5-HT_2A receptor agonists can have varying efficacies for activating these pathways, in turn resulting in different effects.^{[10][11][12][8]} Differing efficacies at different downstream signaling pathways relative to serotonin is also known as functional selectivity or biased agonism.^[10][11]

Serotonin 5-HT_2A receptor agonists are frequently analogues of the neurotransmitter serotonin, and include tryptamines, phenethylamines, and ergolines and lysergamides, among other chemical classes.^[1][13][14]

In addition to the recreational and entheogenic use of serotonergic psychedelics, both psychedelic and non-hallucinogenic serotonin 5-HT_2A receptor agonists, which act as psychoplastogens and have antidepressant-like effects in animals, may have applications in the treatment of psychiatric disorders such as depression, anxiety, and addiction.^[15][16] However, use of psychedelics for such purposes has also been critiqued and their potential adverse effects highlighted.^[17][18][19]

Serotonergic psychedelics

Main articles: Psychedelic drug and Serotonin § Psychedelics

Serotonergic psychedelics, also known as hallucinogenic serotonin 5-HT_2A receptor agonists, produce hallucinogenic effects including open-eye and closed-eye psychedelic visuals, other perceptual changes, synesthesia, time dilation, ego loss, emotional changes, and mystical experiences, among others.^{[20][21][22][23][24]} Examples of serotonergic psychedelics include tryptamines like psilocybin, psilocin, dimethyltryptamine (DMT), and 5-MeO-DMT; phenethylamines like mescaline, 2C-B, DOM, 25I-NBOMe, and MDA; and lysergamides like LSD and ergine (LSA), among others.^[1][13] It is thought that a certain minimum level of activational efficacy at the G_q pathway of the serotonin 5-HT_2A receptor may be required for psychedelic effects.^[10][11][12] However, more research is needed, and a role of other pathways such as the β-arrestin pathway has not been ruled out.^[10][14]

Non-hallucinogenic 5-HT2A receptor agonists

See also: Psychoplastogen and Head-twitch response § Non-hallucinogenic serotonin 5-HT2A receptor agonists

Non-hallucinogenic serotonin 5-HT_2A receptor agonists, which have sometimes been referred to as "non-hallucinogenic psychedelics", are a class of drugs which act as agonists of the serotonin 5-HT_2A receptor and produce effects mediated by this receptor such as neuroplastic and behavioral changes but do not produce psychedelic effects.^{[1][4][16][25][26]} This class of drugs includes the following compounds:^{[1][4][16][25]}

• Tryptamines like 6-fluoro-DET, 6-MeO-DMT, and AET
• Ibogalogs like tabernanthalog (TBG; DLX-007), ibogaminalog (DM-506), noribogainalog (nor-IBG), catharanthalog (CAG), and PNU-22394
• Isotryptamines like isoDMT, 5-MeO-isoDMT, 6-MeO-isoDMT, and zalsupindole (AAZ-A-154; DLX-001; 5-MeO-α-Me-isoDMT)
• Tetrahydropyridinylpyrrolopyridines like (R)-69 and (R)-70
• Phenethylamines like Ariadne (4C-D; BL-3912; Dimoxamine), 5C-D, ASR-2001 (2CB-5PrO), 25N-N1-Nap, and RS130-180
• Ergolines and lysergamides like lisuride, ergotamine, and 2-bromo-LSD (BOL-148)
• Pyridopyrroloquinoxalines like IHCH-7086, IHCH-7079, and ITI-1549

However, most of the above-listed drugs have been concluded to be non-hallucinogenic based on animal behavioral measures of psychedelic-like effects such as the head-twitch response (HTR) assay in rodents. Many of these drugs have not been tested in humans and their putatively non-hallucinogenic natures have not been confirmed. Although available evidence is limited, some observations suggest that hallucinogenic effects may emerge at higher doses in some cases. For instance, while tabernanthalog has been reported to be non-hallucinogenic based on preclinical research, anecdotal reports suggest that it can produce mild hallucinogenic effects at sufficiently high doses in humans.^[27][28][29] Additionally, hallucinations have been observed in humans with high doses of lisuride, which is an often-cited non-hallucinogenic serotonin 5-HT_2A receptor agonist related to LSD, although the nature and mechanisms of these apparent hallucinogenic effects are unclear and dopamine D₂ receptor agonism might alternatively be involved.^[30] Another drug, JRT, is the isoindole analogue of LSD and has reduced or possibly absent psychedelic-like effects in animals.^[31][32]

The precise mechanism by which non-hallucinogenic serotonin 5-HT_2A receptor agonists lack psychedelic effects is uncertain; it is thought that they may not activate the serotonin 5-HT_2A receptor with sufficient efficacy, possibly specifically with regard to the G_q pathway, to produce hallucinogenic effects.^[11] However, many of these drugs have nonetheless been found to produce psychoplastogenic effects mediated by serotonin 5-HT_2A receptor activation and to an equivalent extent as with psychedelics.^{[33][34][35][36]} This might be involved in the antidepressant-like effects of these drugs per animal studies, and non-hallucinogenic serotonin 5-HT_2A receptor agonists may have therapeutic potential similarly to psychedelics.^{[36][37][38][39][40]}

In preclinical models, animals administered non-hallucinogenic serotonin 5-HT_2A receptor agonists exhibit fewer hallucinogen-associated behaviors at doses that produce rapid antidepressant-like effects.^[41][27] The psychoplastogenic effects of non-hallucinogenic serotonin 5-HT_2A receptor agonists appear to coincide with their rapid antidepressant-like effects in animal models.^[40] It has been suggested that non-hallucinogenic serotonin 5-HT_2A receptor agonists may be more suitable for broader clinical use compared to psychedelics because of their reduced perception-altering effects.^[42]

Peripherally selective 5-HT2A receptor agonists

See also: Serotonin 5-HT2A receptor § Peripherally selective agonists, and Peripherally selective drug § List of peripherally selective drugs

Peripherally selective serotonin 5-HT_2A receptor agonists that lack effects on the brain are known.^[1][43][30] Aside from serotonin itself,^[24] α-methylserotonin,^[24][44] and the partially peripherally selective bufotenin (N,N-dimethylserotonin),^[43][14][45] another notable example of a peripherally selective serotonin 5-HT_2A receptor agonist is AL-34662.^[46][47] This drug was investigated for the potential treatment of eye diseases such as ocular hypertension and glaucoma.^[46][47] Ergotamine may also be a peripherally selective serotonin 5-HT_2A receptor agonist, and is used as an obstetric drug and antimigraine agent.^[30][48] Psilocybin and psilocin analogues found in psilocybin-containing mushrooms, including baeocystin, norpsilocin, aeruginascin, and 4-HO-TMT, have been found to be peripherally selective serotonin 5-HT_2A receptor agonists as well.^{[49][50][51][52]}

Selected effects of 5-HT2A receptor agonists

Anti-inflammatory 5-HT_2A receptor agonists

Main article: Serotonin 5-HT2A receptor § Anti-inflammatory effects

Some serotonergic psychedelics, such as (R)-DOI and psilocybin, show highly potent anti-inflammatory effects mediated by serotonin 5-HT_2A receptor activation.^{[53][54][55][56][57]} Other serotonergic psychedelics, such as LSD, are less potent, and yet other psychedelics, like DOTFM, show no anti-inflammatory effects at all.^[54][57][58] Conversely, some serotonin 5-HT_2A receptor agonists, such as 2,5-DMA, have potent anti-inflammatory effects with no apparent psychedelic effects.^[57][59][58] These findings indicate that the psychedelic and anti-inflammatory effects of serotonin 5-HT_2A receptor agonists are mediated by different downstream signaling pathways and are fully dissociable.^[57][59][58] Serotonin 5-HT_2A receptor agonists with reduced psychedelic potential but retained anti-inflammatory effects, such as 2C-iBu (ELE-02), are being studied to treat inflammatory disorders.^[60][61][62]

5-HT_2A receptor agonists and organ fibrosis

See also: Psychedelic microdosing § Long-term toxicity

Many serotonin 5-HT_2A receptor agonists, due to lack of selectivity and activation of the closely related serotonin 5-HT_2B receptor,^[63][8][64] may have the potential to produce organ fibrosis and associated complications such as cardiac valvulopathy or pulmonary hypertension with long-term use.^{[65][66][67][68]} This has been observed with pharmaceutical drugs such as fenfluramine, methysergide, ergotamine, cabergoline, and pergolide, among others, which has led to market withdrawal or restrictions on use of such agents.^{[69][70][71][72][73]} Infrequent or occasional use of serotonergic psychedelics is thought to be safe and not pose a significant risk, but very frequent use or microdosing may carry risk.^[65][67][74] Not all serotonin 5-HT_2A receptor agonists are also potent serotonin 5-HT_2B receptor agonists however.^[63][8][64] For example, many phenethylamine psychedelics show substantial selectivity for the serotonin 5-HT_2A and 5-HT_2C receptors over the serotonin 5-HT_2B receptor.^[63][8][64] In addition, selective serotonin 5-HT_2A receptor agonists that show less or no activation of other serotonin receptors such as the serotonin 5-HT_2B receptor, such as 25CN-NBOH, DMBMPP, LPH-5, and TGF-8027, have been developed.^[1][75][9] Moreover, selective serotonin 5-HT_2B receptor antagonists, including peripherally selective drugs like VU0530244, are being developed, and may be able to block the complications of serotonin 5-HT_2B receptor agonism.^{[71][76][77][78][79]}

Indirect 5-HT2A receptor agonists

See also: 5-HT2A receptor § Serotonin-elevating drugs, Serotonin § Psychedelics, and Psychedelic drug § Mechanism of action

Serotonergic agents that elevate serotonin levels can act as indirect serotonin 5-HT_2A receptor agonists.^[80][81] Examples include serotonin precursors like tryptophan and 5-hydroxytryptophan (5-HTP), serotonin reuptake inhibitors (SRIs) like selective serotonin reuptake inhibitors (SSRIs) and various other antidepressants, monoamine oxidase inhibitors (MAOIs), and serotonin releasing agents like fenfluramine and MDMA.^{[80][81][82][83][84][85][86][87]} Direct serotonin 5-HT_2A receptor agonists and serotonin-elevating drugs have differing effects.^[35] As an example, whereas serotonin-elevating drugs have a risk of serotonin syndrome, major serotonergic psychedelics like psilocybin and LSD are partial agonists of the serotonin 5-HT_2A receptor and have little or no risk of serotonin syndrome even in the context of large overdoses.^[88][89][90] However, one notable group of psychedelics, the NBOMe drugs, have higher efficacy at the serotonin 5-HT_2A receptor and can produce serotonin syndrome.^[89] As another example, serotonin is a highly hydrophilic molecule and is unable to enter neurons and activate intracellular serotonin 5-HT_2A receptors, which have been found to mediate the psychoplastogenic effects and may contribute to the psychedelic effects of exogenous serotonin 5-HT_2A receptor agonists.^[91][35][92]

See also

• Serotonin 5-HT_2A receptor § Agonists
• Serotonin receptor agonist
• Serotonin receptor antagonist
• Serotonin 5-HT_2C receptor agonist
• Serotonin 5-HT₃ receptor antagonist
• List of investigational hallucinogens and entactogens
• Trip killer § Serotonergic psychedelic antidotes