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Serotonin 5-HT2A receptor agonist
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A serotonin 5-HT2A receptor agonist, or simply 5-HT2A agonist, is a drug which acts as an agonist of the serotonin 5-HT2A receptor.[1][2] The serotonin 5-HT2A receptor is one of 13 known human serotonin receptors.[3] Serotonin 5-HT2A receptor agonists can be divided into two main groups: (1) serotonergic psychedelics such as LSD, psilocybin, and mescaline; and (2) non-hallucinogenic serotonin 5-HT2A receptor agonists such as lisuride, Ariadne, tabernanthalog, and zalsupindole, among others.[1][4] Psychedelic and non-hallucinogenic serotonin 5-HT2A receptor agonists can be reliably distinguished from each other in scientific research using the head-twitch response assay in animals.[5][4][6]
Agonists of the serotonin 5-HT2A receptor are generally not selective for this receptor and also interact with other serotonin receptors, such as the serotonin 5-HT1A, 5-HT2B, and/or 5-HT2C receptors, among others.[7][8] However, highly selective serotonin 5-HT2A receptor agonists, such as TGF-8027, have also been developed.[9] In addition to degree of selectivity for the serotonin 5-HT2A receptor, the serotonin 5-HT2A receptor activates a variety of different downstream signaling pathways, such as G protein and β-arrestin cascades, and serotonin 5-HT2A 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-HT2A 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 5-HT2A receptor agonists, which act as psychoplastogens and have antidepressant-like effects in animals, may have applications in the treatment of psychiatric disorders.[15][16] However, such uses have also been critiqued and potential adverse effects highlighted.[17][18][19]
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Serotonergic psychedelics
Serotonergic psychedelics, also known as hallucinogenic serotonin 5-HT2A 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 Gq pathway of the serotonin 5-HT2A 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]
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Non-hallucinogenic 5-HT2A receptor agonists
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Non-hallucinogenic serotonin 5-HT2A receptor agonists include 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), ASR-2001 (2CB-5PrO), 25N-N1-Nap, and RS130-180; ergolines and lysergamides like lisuride, ergotamine, and 2-bromo-LSD (BOL-148); and pyridopyrroloquinoxalines like IHCH-7086, IHCH-7079, and ITI-1549, among others.[1][4][16][25] However, 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.[26][27][28] Another drug, JRT, is the isoindole analogue of LSD and has reduced psychedelic-like effects in animals.[29][30]
It is thought that non-hallucinogenic serotonin 5-HT2A receptor agonists may not activate the serotonin 5-HT2A receptor with sufficient efficacy, possibly specifically with regard to the Gq pathway, to produce psychedelic effects.[11] However, these drugs, including many of the preceding listed agents, have nonetheless been found to produce psychoplastogenic effects mediated by serotonin 5-HT2A receptor activation and to an equivalent extent as with serotonergic psychedelics.[31][32][33][34] This might be involved in the antidepressant-like effects of these drugs and non-hallucinogenic serotonin 5-HT2A receptor agonists may have therapeutic potential similarly to psychedelics.[34][35][36][37]
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Peripherally selective 5-HT2A receptor agonists
Peripherally selective serotonin 5-HT2A receptor agonists that lack effects on the brain are known.[1][38][39] Aside from serotonin itself,[24] α-methylserotonin,[24][40] and the partially peripherally selective bufotenin (N,N-dimethylserotonin),[38][14][41] another notable example of a peripherally selective serotonin 5-HT2A receptor agonist is AL-34662.[42][43] This drug was investigated for the potential treatment of eye diseases such as ocular hypertension and glaucoma.[42][43] Ergotamine may also be a peripherally selective serotonin 5-HT2A receptor agonist, and is used as an obstetric drug and antimigraine agent.[39][44] 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-HT2A receptor agonists as well.[45][46][47][48]
Selected effects of 5-HT2A receptor agonists
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Anti-inflammatory 5-HT2A receptor agonists
Some serotonergic psychedelics, such as (R)-DOI and psilocybin, show highly potent anti-inflammatory effects mediated by serotonin 5-HT2A receptor activation.[49][50][51][52][53] Other serotonergic psychedelics, such as LSD, are less potent, and yet other psychedelics, like DOTFM, show no anti-inflammatory effects at all.[50][53][54] Conversely, some serotonin 5-HT2A receptor agonists, such as 2,5-DMA, have potent anti-inflammatory effects with no apparent psychedelic effects.[53][55][54] These findings indicate that the psychedelic and anti-inflammatory effects of serotonin 5-HT2A receptor agonists are mediated by different downstream signaling pathways and are fully dissociable.[53][55][54] Serotonin 5-HT2A receptor agonists with reduced psychedelic potential but retained anti-inflammatory effects, such as 2C-iBu (ELE-02), are being studied to treat inflammatory disorders.[56][57][58]
5-HT2A receptor agonists and organ fibrosis
Many serotonin 5-HT2A receptor agonists, due to lack of selectivity and activation of the closely related serotonin 5-HT2B receptor,[59][8][60] may have the potential to produce organ fibrosis and associated complications such as cardiac valvulopathy or pulmonary hypertension with long-term use.[61][62][63][64] 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.[65][66][67][68][69] 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.[61][63][70] Not all serotonin 5-HT2A receptor agonists are also potent serotonin 5-HT2B receptor agonists however.[59][8][60] For example, many phenethylamine psychedelics show substantial selectivity for the serotonin 5-HT2A and 5-HT2C receptors over the serotonin 5-HT2B receptor.[59][8][60] In addition, selective serotonin 5-HT2A receptor agonists that show less or no activation of other serotonin receptors such as the serotonin 5-HT2B receptor, such as 25CN-NBOH, DMBMPP, LPH-5, and TGF-8027, have been developed.[1][71][9] Moreover, selective serotonin 5-HT2B receptor antagonists, including peripherally selective drugs like VU0530244, are being developed, and may be able to block the complications of serotonin 5-HT2B receptor agonism.[67][72][73][74][75]
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Indirect 5-HT2A receptor agonists
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Serotonergic agents that elevate serotonin levels can act as indirect serotonin 5-HT2A receptor agonists.[76][77] 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.[76][77][78][79][80][81][82][83] Direct serotonin 5-HT2A receptor agonists and serotonin-elevating drugs have differing effects.[33] 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-HT2A receptor and have little or no risk of serotonin syndrome even in the context of large overdoses.[84][85][86] However, one notable group of psychedelics, the NBOMe drugs, have higher efficacy at the serotonin 5-HT2A receptor and can produce serotonin syndrome.[85] As another example, serotonin is a highly hydrophilic molecule and is unable to enter neurons and activate intracellular serotonin 5-HT2A receptors, which have been found to mediate the psychoplastogenic effects and may contribute to the psychedelic effects of exogenous serotonin 5-HT2A receptor agonists.[87][33][88]
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