Editing Serotonin (section)

===Psychedelics===
{{See also|Psychedelic drug#Mechanism of action}}

[[Serotonergic psychedelic]]s, including drugs like [[psilocybin]] (found in [[psilocybin mushroom]]s), [[dimethyltryptamine]] (DMT) (found in [[ayahuasca]]), [[lysergic acid diethylamide]] (LSD), [[mescaline]] (found in [[peyote|peyote cactus]]), and [[5-MeO-DMT]] (found in ''[[Anadenanthera]]'' trees and the ''[[Bufo alvarius]]'' toad), are [[binding selectivity|non-selective]] [[agonist]]s of the [[serotonin receptor]]s and mediate their [[hallucinogen]]ic effects specifically by activation of the serotonin [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]].<ref name="SlocumDiBertoRoth2022">{{cite journal | vauthors = Slocum ST, DiBerto JF, Roth BL | title = Molecular insights into psychedelic drug action | journal = J Neurochem | volume = 162 | issue = 1 | pages = 24–38 | date = July 2022 | pmid = 34797943 | doi = 10.1111/jnc.15540 | url = }}</ref><ref name="DuanCaoWang2024">{{cite journal | vauthors = Duan W, Cao D, Wang S, Cheng J | title = Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants | journal = Chem Rev | volume = 124 | issue = 1 | pages = 124–163 | date = January 2024 | pmid = 38033123 | doi = 10.1021/acs.chemrev.3c00375 | url = }}</ref><ref name="Nichols2018">{{cite book | vauthors = Nichols DE | title = Chemistry and Structure-Activity Relationships of Psychedelics | series = Current Topics in Behavioral Neurosciences | volume = 36 | pages = 1–43 | date = 2018 | pmid = 28401524 | doi = 10.1007/7854_2017_475 | isbn = 978-3-662-55878-2 | url = }}</ref> This is evidenced by the fact that serotonin 5-HT<sub>2A</sub> receptor antagonists and so-called "[[trip killer]]s" like [[ketanserin]] block the hallucinogenic effects of serotonergic psychedelics in humans, among many other findings.<ref name="SlocumDiBertoRoth2022" /><ref name="DuanCaoWang2024" /><ref name="HalmanKongSarris2024">{{Cite journal |vauthors=Halman A, Kong G, Sarris J, Perkins D |date=January 2024 |title=Drug-drug interactions involving classic psychedelics: A systematic review |journal=J Psychopharmacol |volume=38 |issue=1 |pages=3–18 |doi=10.1177/02698811231211219 |pmc=10851641 |pmid=37982394}}</ref> Some serotonergic psychedelics, like [[psilocin]], DMT, and 5-MeO-DMT, are [[substituted tryptamine]]s and are very similar in [[chemical structure]] to serotonin.<ref name="Nichols2018" />

Serotonin itself, despite acting as a serotonin 5-HT<sub>2A</sub> receptor agonist, is thought to be non-hallucinogenic.<ref name="VargasDunlapDong2023" /> The hallucinogenic effects of serotonergic psychedelics appear to be mediated by activation of serotonin 5-HT<sub>2A</sub> receptors expressed in a population of [[Cerebral cortex|cortical]] [[neuron]]s in the [[medial prefrontal cortex]] (mPFC).<ref name="Sapienza2023">{{cite journal | vauthors = Sapienza J | title=The Key Role of Intracellular 5-HT2A Receptors: A Turning Point in Psychedelic Research? | journal=Psychoactives | volume=2 | issue=4 | date=13 October 2023 | issn=2813-1851 | doi=10.3390/psychoactives2040018 | doi-access=free | pages=287–293}}</ref><ref name="VargasDunlapDong2023">{{cite journal | vauthors = Vargas MV, Dunlap LE, Dong C, Carter SJ, Tombari RJ, Jami SA, Cameron LP, Patel SD, Hennessey JJ, Saeger HN, McCorvy JD, Gray JA, Tian L, Olson DE | title = Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors | journal = Science | volume = 379 | issue = 6633 | pages = 700–706 | date = February 2023 | pmid = 36795823 | pmc = 10108900 | doi = 10.1126/science.adf0435 | bibcode = 2023Sci...379..700V | url = | quote = In addition to promoting psychedelic-induced structural neuroplasticity, the intracellular population of 5-HT2ARs might also contribute to the hallucinogenic effects of psychedelics. When we administered a serotonin-releasing agent to wild type mice, we did not observe a HTR. However, the same drug was able to induce a HTR in mice expressing SERT on cortical neurons of the mPFC—a brain region known to be essential for the HTR (49). Thus, activation of intracellular cortical 5-HT2ARs may play a role in the subjective effects of psychedelics. This hypothesis is further supported by previous work demonstrating that a high dose of the serotonin precursor 5-hydroxytryptophan (5-HTP) induces a HTR in WT mice, which can be blocked by an N-methyltransferase inhibitor that prevents the metabolism of 5-HTP to N-methyltryptamines (50). Inhibition of N-methyltransferase failed to block the HTR induced by 5-MeO-DMT (50). Taken together, this work emphasizes that accessing intracellular 5-HT2ARs is important for 5-HT2AR agonists to produce a HTR.}}</ref> These serotonin 5-HT<sub>2A</sub> receptors, unlike most serotonin and related receptors, are expressed [[intracellular]]ly.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> In addition, the neurons containing them lack [[gene expression|expression]] of the [[serotonin transporter]] (SERT), which normally [[active transport|transport]]s serotonin from the [[extracellular]] space to the intracellular space within neurons.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> Serotonin itself is too [[hydrophilic]] to enter serotonergic neurons without the SERT, and hence these serotonin 5-HT<sub>2A</sub> receptors are inaccessible to serotonin.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> Conversely, serotonergic psychedelics are more [[lipophilic]] than serotonin and readily enter these neurons.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> In addition to explaining why serotonin does not show psychedelic effects, these findings may explain why drugs that increase serotonin levels, like [[selective serotonin reuptake inhibitor]]s (SSRIs) and various other types of serotonergic agents, do not produce psychedelic effects.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> Artificial expression of the SERT in these medial prefrontal cortex neurons resulted in the [[serotonin releasing agent]] [[para-chloroamphetamine|''para''-chloroamphetamine]] (PCA), which does not normally show psychedelic-like effects, being able to produce psychedelic-like effects in animals.<ref name="VargasDunlapDong2023" />

Although serotonin itself is non-hallucinogenic, administration of very high doses of a [[serotonin precursor]], like [[tryptophan]] or [[5-hydroxytryptophan]] (5-HTP), or [[intracerebroventricular injection]] of high doses of serotonin directly into the brain, can produce psychedelic-like effects in animals.<ref name="SchmidBohn2018">{{cite book | vauthors = Schmid CL, Bohn LM | title=5-HT2A Receptors in the Central Nervous System | chapter=βArrestins: Ligand-Directed Regulators of 5-HT2A Receptor Trafficking and Signaling Events | publisher=Springer International Publishing | publication-place=Cham | date=2018 | isbn=978-3-319-70472-2 | doi=10.1007/978-3-319-70474-6_2 | pages=31–55}}</ref><ref name="KozlenkovGonzález-Maeso2013">{{cite book |  vauthors = Kozlenkov A, González-Maeso J | title=The Neuroscience of Hallucinations | chapter=Animal Models and Hallucinogenic Drugs | publisher=Springer New York | publication-place=New York, NY | date=2013 | isbn=978-1-4614-4120-5 | doi=10.1007/978-1-4614-4121-2_14 | pages=253–277}}</ref><ref name="SchmidBohn2010">{{cite journal | vauthors = Schmid CL, Bohn LM | title = Serotonin, but not N-methyltryptamines, activates the serotonin 2A receptor via a β-arrestin2/Src/Akt signaling complex in vivo | journal = J Neurosci | volume = 30 | issue = 40 | pages = 13513–24 | date = October 2010 | pmid = 20926677 | pmc = 3001293 | doi = 10.1523/JNEUROSCI.1665-10.2010 | url = }}</ref> These psychedelic-like effects can be abolished by [[indolethylamine N-methyltransferase|indolethylamine ''N''-methyltransferase]] (INMT) [[enzyme inhibitor|inhibitor]]s, which block conversion of serotonin and other endogenous tryptamines into ''N''-[[methyl group|methylated]] tryptamines, including [[N-Methylserotonin|''N''-methylserotonin]] (NMS; norbufotenin), [[bufotenin]] (5-hydroxy-''N'',''N''-dimethyltryptamine; 5-HO-DMT), [[N-methyltryptamine|''N''-methyltryptamine]] (NMT), and [[dimethyltryptamine|''N'',''N''-dimethyltryptamine]] (DMT).<ref name="KozlenkovGonzález-Maeso2013" /><ref name="HalberstadtGeyer2018">{{cite book | vauthors = Halberstadt AL, Geyer MA | title = Behavioral Neurobiology of Psychedelic Drugs | chapter = Effect of Hallucinogens on Unconditioned Behavior | series = Current Topics in Behavioral Neurosciences | volume = 36 | pages = 159–199 | date = 2018 | pmid = 28224459 | pmc = 5787039 | doi = 10.1007/7854_2016_466 | isbn = 978-3-662-55878-2 | chapter-url = }}</ref><ref name="SchmidBohn2010" /> These ''N''-methyltryptamines are much more lipophilic than serotonin and, in contrast, are able to [[passive diffusion|diffuse]] into serotonergic neurons and activate intracellular serotonin 5-HT<sub>2A</sub> receptors.<ref name="KozlenkovGonzález-Maeso2013" /><ref name="SchmidBohn2010" /><ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" /> Another possible metabolite of serotonin with psychedelic-like effects in animals is [[5-methoxytryptamine]] (5-MT).<ref name="Pévet1983">{{cite journal | vauthors = Pévet P | title = Is 5-methoxytryptamine a pineal hormone? | journal = Psychoneuroendocrinology | volume = 8 | issue = 1 | pages = 61–73 | date = 1983 | pmid = 6136058 | doi = 10.1016/0306-4530(83)90041-0 | url = }}</ref><ref name="TanHardelandBack2016">{{cite journal | vauthors = Tan DX, Hardeland R, Back K, Manchester LC, Alatorre-Jimenez MA, Reiter RJ | title = On the significance of an alternate pathway of melatonin synthesis via 5-methoxytryptamine: comparisons across species | journal = J Pineal Res | volume = 61 | issue = 1 | pages = 27–40 | date = August 2016 | pmid = 27112772 | doi = 10.1111/jpi.12336 | url = }}</ref><ref name="PrzegalińskiZebrowska-LupinaWójcik1977">{{cite journal | vauthors = Przegaliński E, Zebrowska-Lupina I, Wójcik A, Kleinrok Z | title = 5-Methoxytryptamine-induced head twitches in rats | journal = Pol J Pharmacol Pharm | volume = 29 | issue = 3 | pages = 253–261 | date = 1977 | pmid = 267911 | doi = | url = }}</ref>

DMT is a [[natural product|naturally occurring]] [[endogenous]] compound in the body.<ref name="JiménezBouso2022">{{cite journal | vauthors = Jiménez JH, Bouso JC | title = Significance of mammalian N, N-dimethyltryptamine (DMT): A 60-year-old debate | journal = J Psychopharmacol | volume = 36 | issue = 8 | pages = 905–919 | date = August 2022 | pmid = 35695604 | doi = 10.1177/02698811221104054 | url = }}</ref><ref name="Barker2018">{{cite journal | vauthors = Barker SA | title = N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen: Past, Present, and Future Research to Determine Its Role and Function | journal = Front Neurosci | volume = 12 | issue = | pages = 536 | date = 2018 | pmid = 30127713 | pmc = 6088236 | doi = 10.3389/fnins.2018.00536 | doi-access = free | url = }}</ref><ref name="CameronOlson2018">{{cite journal | vauthors = Cameron LP, Olson DE | title = Dark Classics in Chemical Neuroscience: N, N-Dimethyltryptamine (DMT) | journal = ACS Chem Neurosci | volume = 9 | issue = 10 | pages = 2344–2357 | date = October 2018 | pmid = 30036036 | doi = 10.1021/acschemneuro.8b00101 | url = }}</ref> In relation to the fact that serotonin itself is unable to activate intracellular serotonin 5-HT<sub>2A</sub> receptors, it is possible that DMT might be the endogenous [[ligand (biochemistry)|ligand]] of these receptors rather than serotonin.<ref name="Sapienza2023" /><ref name="VargasDunlapDong2023" />