Editing LSD (section)

==Pharmacology==
===Pharmacodynamics===
[[File:LSDaffinities.GIF|class=skin-invert-image|thumb|right|300px|[[Affinity (pharmacology)|Affinities]] (K<sub>i</sub>) of LSD for various [[receptor (biochemistry)|receptor]]s. The lower the value, the more strongly LSD binds to that receptor (i.e., with higher affinity). The horizontal line represents an approximate value for human plasma concentrations of LSD, and hence, affinities that are above the line are unlikely to be involved in LSD's effects. Values are averages the [[Ki Database|K<sub>i</sub> Database]].<ref name="PDSPKiDatabase" />]]

{| class="wikitable floatright" style="font-size:small;"
|+ {{Nowrap|Activities of LSD}}
|-
! [[Biological target|Target]] !! [[Affinity (pharmacology)|Affinity]] (K<sub>i</sub>, nM)
|-
| [[5-HT1A receptor|5-HT<sub>1A</sub>]] || 0.64–7.3 (K<sub>i</sub>)<br />6.4 ({{Abbrlink|EC<sub>50</sub>|half-maximal effective concentration}})<br />110% ({{Abbrlink|E<sub>max</sub>|maximal efficacy}})
|-
| [[5-HT1B receptor|5-HT<sub>1B</sub>]] || 3.9
|-
| [[5-HT1D receptor|5-HT<sub>1D</sub>]] || 3.9–14
|-
| [[5-HT1E receptor|5-HT<sub>1E</sub>]] || 93
|-
| [[5-HT1F receptor|5-HT<sub>1F</sub>]] || {{Abbr|ND|No data}}
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub>]] || 0.47–21 (K<sub>i</sub>)<br />0.24–538 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}})<br />23–88% ({{Abbr|E<sub>max</sub>|maximal efficacy}})
|-
| [[5-HT2B receptor|5-HT<sub>2B</sub>]] || 0.98–30 (K<sub>i</sub>)<br />0.68–12,000 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}})<br />13–73% ({{Abbr|E<sub>max</sub>|maximal efficacy}})
|-
| [[5-HT2C receptor|5-HT<sub>2C</sub>]] || 1.1–48 (K<sub>i</sub>)<br />0.85–1,590 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}})<br />26–79% ({{Abbr|E<sub>max</sub>|maximal efficacy}})
|-
| [[5-HT3 receptor|5-HT<sub>3</sub>]] || >10,000
|-
| [[5-HT4 receptor|5-HT<sub>4</sub>]] || 1,000 (rat)
|-
| [[5-HT5A receptor|5-HT<sub>5A</sub>]] || 9.0
|-
| [[5-HT5B receptor|5-HT<sub>5B</sub>]] || 3.2 (rat)
|-
| [[5-HT6 receptor|5-HT<sub>6</sub>]] || 2.3–6.9
|-
| [[5-HT7 receptor|5-HT<sub>7</sub>]] || 6.3–6.6
|-
| [[Alpha-1A adrenergic receptor|α<sub>1A</sub>]] || 670–1,128
|-
| [[Alpha-1B adrenergic receptor|α<sub>1B</sub>]] || 8,677
|-
| [[Alpha-1D adrenergic receptor|α<sub>1D</sub>]] || {{Abbr|ND|No data}}
|-
| [[Alpha-2A adrenergic receptor|α<sub>2A</sub>]] || 12–46
|-
| [[Alpha-2B adrenergic receptor|α<sub>2B</sub>]], [[Alpha-2C adrenergic receptor|α<sub>2C</sub>]] || {{Abbr|ND|No data}}
|-
| [[Beta-1 adrenergic receptor|β<sub>1</sub>]] || 140–1,601
|-
| [[Beta-2 adrenergic receptor|β<sub>2</sub>]] || 740–3,461
|-
| [[Beta-3 adrenergic receptor|β<sub>3</sub>]] || {{Abbr|ND|No data}}
|-
| [[D1 receptor|D<sub>1</sub>]] || 155–340 (K<sub>i</sub>)<br />35–63 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}})<br />35–44% ({{Abbr|E<sub>max</sub>|maximal efficacy}})
|-
| [[D2 receptor|D<sub>2</sub>]] || 61–126
|-
| [[D3 receptor|D<sub>3</sub>]] || 27–60
|-
| [[D4 receptor|D<sub>4</sub>]] || 26–158
|-
| [[D5 receptor|D<sub>5</sub>]] || 75–344
|-
| [[H1 receptor|H<sub>1</sub>]] || 1,100–1,540
|-
| [[H2 receptor|H<sub>2</sub>]]–[[H4 receptor|H<sub>4</sub>]] || {{Abbr|ND|No data}}
|-
| [[Muscarinic acetylcholine M1 receptor|M<sub>1</sub>]]–[[Muscarinic acetylcholine M5 receptor|M<sub>5</sub>]] || {{Abbr|ND|No data}}
|-
| [[I1 receptor|I<sub>1</sub>]] || {{Abbr|ND|No data}}
|-
| [[Sigma-1 receptor|σ<sub>1</sub>]], [[Sigma-2 receptor|σ<sub>2</sub>]] || {{Abbr|ND|No data}}
|-
| [[Trace amine-associated receptor 1|TAAR1]] || 450 (K<sub>i</sub>) (rat)<br />10,000 (K<sub>i</sub>) (mouse)<br />1,400 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}}) (rat)<br />9,700 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}}) (mouse)<br />>20,000 ({{Abbr|EC<sub>50</sub>|half-maximal effective concentration}}) (human)
|-
| {{Abbrlink|SERT|Serotonin transporter}} || >30,000 (K<sub>i</sub>)<br />>100,000 ({{Abbrlink|IC<sub>50</sub>|half-maximal inhibitory concentration}})
|-
| {{Abbrlink|NET|Norepinephrine transporter}} || 5,600–>30,000 (K<sub>i</sub>)<br />>100,000 ({{Abbr|IC<sub>50</sub>|half-maximal inhibitory concentration}})
|-
| {{Abbrlink|DAT|Dopamine transporter}} || >30,000 (K<sub>i</sub>)<br />>100,000 ({{Abbr|IC<sub>50</sub>|half-maximal inhibitory concentration}})
|- class="sortbottom"
| colspan="2" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise noted. '''Refs:''' <ref name="PDSPKiDatabase">{{cite web | title=PDSP Database | website=UNC | url=https://pdsp.unc.edu/databases/pdsp.php?testFreeRadio=testFreeRadio&testLigand=lsd&kiAllRadio=all&doQuery=Submit+Query | language=zu | access-date=11 December 2024}}</ref><ref name="BindingDB">{{cite web | vauthors = Liu T | title=BindingDB BDBM21342 (4R,7R)-N,N-diethyl-6-methyl-6,11-diazatetracyclo[7.6.1.0^{2,7}.0^{12,16}]hexadeca-1(16),2,9,12,14-pentaene-4-carboxamide::CHEMBL263881::LSD::LSD 25::LSD,(+)::LSD,l-::Lysergic Acid Diethylamide::Lysergic Acid Diethylamide Tartrate::US20240166618, Compound LSD::[3H]-LSD::d-Isolysergic acid amide | website=BindingDB | url=https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=21342 | access-date=11 December 2024}}</ref><ref name="HolzeSinghLiechti2024">{{cite journal | vauthors = Holze F, Singh N, Liechti ME, D'Souza DC | title = Serotonergic Psychedelics: A Comparative Review of Efficacy, Safety, Pharmacokinetics, and Binding Profile | journal = Biol Psychiatry Cogn Neurosci Neuroimaging | volume = 9 | issue = 5 | pages = 472–489 | date = May 2024 | pmid = 38301886 | doi = 10.1016/j.bpsc.2024.01.007 | url = | doi-access = free }}</ref><ref name="Ray2010">{{cite journal | vauthors = Ray TS | title = Psychedelics and the human receptorome | journal = PLOS ONE | volume = 5 | issue = 2 | pages = e9019 | date = February 2010 | pmid = 20126400 | pmc = 2814854 | doi = 10.1371/journal.pone.0009019 | doi-access = free | bibcode = 2010PLoSO...5.9019R | url = }}</ref><ref name="RickliLuethiReinisch2015">{{cite journal | vauthors = Rickli A, Luethi D, Reinisch J, Buchy D, Hoener MC, Liechti ME | title = Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs) | journal = Neuropharmacology | volume = 99 | issue = | pages = 546–553 | date = December 2015 | pmid = 26318099 | doi = 10.1016/j.neuropharm.2015.08.034 | url = http://edoc.unibas.ch/56163/1/20170921163006_59c3cceeb8e5d.pdf}}</ref><ref name="RickliMoningHoener2016">{{cite journal | vauthors = Rickli A, Moning OD, Hoener MC, Liechti ME | title = Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens | journal = Eur Neuropsychopharmacol | volume = 26 | issue = 8 | pages = 1327–1337 | date = August 2016 | pmid = 27216487 | doi = 10.1016/j.euroneuro.2016.05.001 | url = http://edoc.unibas.ch/53326/1/20170117174852_587e4af45b658.pdf}}</ref><ref name="LuethiTrachselHoener2018">{{cite journal | vauthors = Luethi D, Trachsel D, Hoener MC, Liechti ME | title = Monoamine receptor interaction profiles of 4-thio-substituted phenethylamines (2C-T drugs) | journal = Neuropharmacology | volume = 134 | issue = Pt A | pages = 141–148 | date = May 2018 | pmid = 28720478 | doi = 10.1016/j.neuropharm.2017.07.012 | url = https://edoc.unibas.ch/57358/1/20170920150712_59c2680084ec5.pdf}}</ref><ref name="EshlemanForsterWolfrum2014">{{cite journal | vauthors = Eshleman AJ, Forster MJ, Wolfrum KM, Johnson RA, Janowsky A, Gatch MB | title = Behavioral and neurochemical pharmacology of six psychoactive substituted phenethylamines: mouse locomotion, rat drug discrimination and in vitro receptor and transporter binding and function | journal = Psychopharmacology (Berl) | volume = 231 | issue = 5 | pages = 875–888 | date = March 2014 | pmid = 24142203 | pmc = 3945162 | doi = 10.1007/s00213-013-3303-6 | url = https://www.researchgate.net/publication/258061356}}</ref><br /><ref name="JanowskyEshlemanJohnson2014">{{cite journal | vauthors = Janowsky A, Eshleman AJ, Johnson RA, Wolfrum KM, Hinrichs DJ, Yang J, Zabriskie TM, Smilkstein MJ, Riscoe MK | title = Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro | journal = Psychopharmacology (Berl) | volume = 231 | issue = 14 | pages = 2771–2783 | date = July 2014 | pmid = 24488404 | pmc = 4097020 | doi = 10.1007/s00213-014-3446-0 | url = }}</ref><ref name="Wsół2023">{{cite journal | vauthors = Wsół A | title = Cardiovascular safety of psychedelic medicine: current status and future directions | journal = Pharmacol Rep | volume = 75 | issue = 6 | pages = 1362–1380 | date = December 2023 | pmid = 37874530 | pmc = 10661823 | doi = 10.1007/s43440-023-00539-4 | url = }}</ref><ref name="EganGrindeDupre2000">{{cite journal | vauthors = Egan C, Grinde E, Dupre A, Roth BL, Hake M, Teitler M, Herrick-Davis K | title = Agonist high and low affinity state ratios predict drug intrinsic activity and a revised ternary complex mechanism at serotonin 5-HT(2A) and 5-HT(2C) receptors | journal = Synapse | volume = 35 | issue = 2 | pages = 144–150 | date = February 2000 | pmid = 10611640 | doi = 10.1002/(SICI)1098-2396(200002)35:2<144::AID-SYN7>3.0.CO;2-K | url = }}</ref><ref name="WackerWangMcCorvy2017">{{cite journal | vauthors = Wacker D, Wang S, McCorvy JD, Betz RM, Venkatakrishnan AJ, Levit A, Lansu K, Schools ZL, Che T, Nichols DE, Shoichet BK, Dror RO, Roth BL | title = Crystal Structure of an LSD-Bound Human Serotonin Receptor | journal = Cell | volume = 168 | issue = 3 | pages = 377–389.e12 | date = January 2017 | pmid = 28129538 | doi = 10.1016/j.cell.2016.12.033 | url = | pmc = 5289311 }}</ref><ref name="McCorvy2013">{{cite thesis | vauthors = McCorvy JD | title=Mapping the binding site of the 5-HT2A receptor using mutagenesis and ligand libraries: Insights into the molecular actions of psychedelics | degree = Ph.D. | publisher = Purdue University | via = Purdue e-Pubs | date=16 January 2013 | url=https://docs.lib.purdue.edu/dissertations/AAI3545320/ | archive-url=https://web.archive.org/web/20250325000000/https://docs.lib.purdue.edu/dissertations/AAI3545320/ | archive-date=25 March 2025 | quote=Table 5.2 Binding affinities using 3 H-LSD at 5-HT2A EL2 mutants [...] Table B.1 Binding affinities for 5-HT2A, 5-HT2C, 5-HT1A receptors using 3 H-LSD [...]}} [https://bitnest.netfirms.com/external/Theses/McCorvey2012 Alt URL]</ref><ref name="PorterBenwellLamb1999">{{cite journal | vauthors = Porter RH, Benwell KR, Lamb H, Malcolm CS, Allen NH, Revell DF, Adams DR, Sheardown MJ | title = Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells | journal = Br J Pharmacol | volume = 128 | issue = 1 | pages = 13–20 | date = September 1999 | pmid = 10498829 | pmc = 1571597 | doi = 10.1038/sj.bjp.0702751 | url = }}</ref><ref name="GainetdinovHoenerBerry2018">{{cite journal | vauthors = Gainetdinov RR, Hoener MC, Berry MD | title = Trace Amines and Their Receptors | journal = Pharmacol Rev | volume = 70 | issue = 3 | pages = 549–620 | date = July 2018 | pmid = 29941461 | doi = 10.1124/pr.117.015305 | url = | doi-access = free }}</ref><ref name="SimmlerBuchyChaboz2016">{{cite journal | vauthors = Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME | title = In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1 | journal = J Pharmacol Exp Ther | volume = 357 | issue = 1 | pages = 134–144 | date = April 2016 | pmid = 26791601 | doi = 10.1124/jpet.115.229765 | url = https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA | archive-url = https://web.archive.org/web/20250509235235/https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA | url-status = dead | archive-date = 2025-05-09 }}</ref>
|}

LSD is a [[serotonergic psychedelic]] and acts as a [[binding selectivity|non-selective]] [[serotonin receptor modulator]].<ref name="Nichols2018a" /> It binds with high [[affinity (pharmacology)|affinity]] to most of the [[serotonin receptor]]s.<ref name="HolzeSinghLiechti2024" /> The [[psychedelic drug|psychedelic]] effects of LSD are thought to be mediated specifically by activation of the [[serotonin]] [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]].<ref name="Nichols2018a" /><ref name="HolzeSinghLiechti2024" /> However, a role of other serotonin receptors and [[biological target|target]]s in the effects of LSD cannot be ruled out and may be considered likely.<ref name="HalberstadtGeyer2011">{{cite journal | vauthors = Halberstadt AL, Geyer MA | title = Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens | journal = Neuropharmacology | volume = 61 | issue = 3 | pages = 364–381 | date = September 2011 | pmid = 21256140 | pmc = 3110631 | doi = 10.1016/j.neuropharm.2011.01.017 | url = }}</ref> Uniquely among serotonergic psychedelics, LSD also shows potentially significant affinity for the [[dopamine receptor]]s, albeit much lower than for most of the serotonin receptors.<ref name="HolzeSinghLiechti2024" /><ref name="Marona-LewickaThistedNichols2005">{{cite journal | vauthors = Marona-Lewicka D, Thisted RA, Nichols DE | title = Distinct temporal phases in the behavioral pharmacology of LSD: dopamine D2 receptor-mediated effects in the rat and implications for psychosis | journal = Psychopharmacology | volume = 180 | issue = 3 | pages = 427–435 | date = July 2005 | pmid = 15723230 | doi = 10.1007/s00213-005-2183-9 | s2cid = 23565306 }}</ref>

LSD binds to most serotonin receptor subtypes except for the serotonin [[5-HT3 receptor|5-HT<sub>3</sub>]] and [[5-HT4 receptor|5-HT<sub>4</sub> receptor]]s.<ref name="HolzeSinghLiechti2024" /> However, some of these serotonin receptors may not be affected at typical brain concentrations of LSD.<ref name="pmid14761703"/> In humans, recreational doses of LSD may affect [[5-HT1A receptor|5-HT<sub>1A</sub>]], [[5-HT2A receptor|5-HT<sub>2A</sub>]], [[5-HT2B receptor|5-HT<sub>2B</sub>]], [[5-HT2C receptor|5-HT<sub>2C</sub>]], [[5-HT5A receptor|5-HT<sub>5A</sub>]], and [[5-HT6 receptor|5-HT<sub>6</sub> receptors]].<ref name="Aghajanian" /> Although not present in humans, [[5-HT5B receptor|5-HT<sub>5B</sub> receptors]] found in rodents also have a high affinity for LSD.<ref name="Nelson2004">{{cite journal |vauthors=Nelson DL |title=5-HT5 receptors |journal=Current Drug Targets. CNS and Neurological Disorders |volume=3 |issue=1 |pages=53–58 |date=February 2004 |pmid=14965244 |doi=10.2174/1568007043482606}}</ref> The psychedelic effects of LSD are attributed to activation of 5-HT<sub>2A</sub> receptors.<ref>{{cite journal |vauthors=Moreno JL, Holloway T, Albizu L, Sealfon SC, González-Maeso J |title=Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists |journal=Neuroscience Letters |volume=493 |issue=3 |pages=76–79 |date=April 2011 |pmid=21276828 |pmc=3064746 |doi=10.1016/j.neulet.2011.01.046}}</ref> Many but not all serotonin 5-HT<sub>2A</sub> [[agonist]]s are [[psychedelics]] and serotonin 5-HT<sub>2A</sub> [[Receptor antagonist|antagonists]] block the psychedelic activity of LSD. LSD exhibits [[functional selectivity]] at the serotonin 5-HT<sub>2A</sub> and 5-HT<sub>2C</sub> receptors in that it activates the [[signal transduction]] enzyme [[phospholipase A2]] instead of activating the enzyme [[phospholipase C]] as the endogenous ligand serotonin does.<ref>{{cite journal |vauthors=Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H, Javitch JA, Roth BL, Christopoulos A, Sexton PM, Miller KJ, Spedding M, Mailman RB |title=Functional selectivity and classical concepts of quantitative pharmacology |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=320 |issue=1 |pages=1–13 |date=January 2007 |pmid=16803859 |doi=10.1124/jpet.106.104463 |url=https://jpet.aspetjournals.org/content/320/1/1 |s2cid=447937 |access-date=June 11, 2023 |archive-date=June 11, 2023 |archive-url=https://web.archive.org/web/20230611010342/https://jpet.aspetjournals.org/content/320/1/1 |url-status=live }}</ref>

Exactly how LSD produces its effects is unknown, but it is thought that it works by increasing [[Glutamate (neurotransmitter)|glutamate]] release in the [[cerebral cortex]]<ref name="pmid14761703"/> and therefore [[Excitatory postsynaptic potential|excitation]] in this area, specifically in [[Cortical layers|layer V]].<ref>{{cite journal | vauthors = Aghajanian GK, Marek GJ | title = Serotonin and hallucinogens | journal = Neuropsychopharmacology | volume = 21 | issue = 2 Suppl | pages = 16S–23S | date = August 1999 | pmid = 10432484 | doi = 10.1016/S0893-133X(98)00135-3 | doi-access = free }}</ref> LSD, like many other drugs of recreational use, has been shown to activate [[DARPP-32]]-related pathways.<ref>{{cite journal | vauthors = Svenningsson P, Nairn AC, Greengard P | title = DARPP-32 mediates the actions of multiple drugs of abuse | journal = The AAPS Journal | volume = 7 | issue = 2 | pages = E353-60 | date = October 2005 | pmid = 16353915 | pmc = 2750972 | doi = 10.1208/aapsj070235 }}</ref> The drug enhances dopamine D<sub>2</sub> receptor [[protomer]] recognition and [[cell signaling|signaling]] of D<sub>2</sub>–5-HT<sub>2A</sub> receptor complexes,<ref name="pmid24309097">{{cite journal | vauthors = Borroto-Escuela DO, Romero-Fernandez W, Narvaez M, Oflijan J, Agnati LF, Fuxe K | title = Hallucinogenic 5-HT2AR agonists LSD and DOI enhance dopamine D2R protomer recognition and signaling of D2-5-HT2A heteroreceptor complexes | journal = Biochemical and Biophysical Research Communications | volume = 443 | issue = 1 | pages = 278–84 | date = January 2014 | pmid = 24309097 | doi = 10.1016/j.bbrc.2013.11.104 }}</ref> which may contribute to its psychotropic effects.<ref name="pmid24309097" /> LSD has been shown to have low affinity for [[H1 receptors]], displaying antihistamine effects, although the significance of this at doses used in humans is unknown.<ref>{{cite journal | vauthors = Green JP, Johnson CL, Weinstein H, Maayani S | title = Antagonism of histamine-activated adenylate cyclase in brain by D-lysergic acid diethylamide | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 74 | issue = 12 | pages = 5697–701 | date = December 1977 | pmid = 23536 | pmc = 431860 | doi = 10.1073/pnas.74.12.5697 | bibcode = 1977PNAS...74.5697G | doi-access = free }}</ref><ref name="synth2"/>

LSD is a [[biased agonist]] that induces a conformation in serotonin receptors that preferentially recruits [[β-arrestin]] over [[Gs alpha subunit|activating G protein]]s.<ref name="Chen_2017">{{cite journal |vauthors=Chen Q, Tesmer JJ |title=A Receptor on Acid |journal=Cell |volume=168 |issue=3 |pages=339–341 |date=January 2017 |doi=10.1016/j.cell.2017.01.012 |pmid=28129534 |pmc=5520807}}</ref> LSD also has an exceptionally long [[residence time#Pharmacology|residence time]] when bound to serotonin receptors lasting hours, consistent with the long-lasting effects of LSD despite its relatively rapid [[clearance (pharmacology)|clearance]].<ref name="RothGumpper2023">{{cite journal | vauthors = Roth BL, Gumpper RH | title = Psychedelics as Transformative Therapeutics | journal = Am J Psychiatry | volume = 180 | issue = 5 | pages = 340–347 | date = May 2023 | pmid = 37122272 | doi = 10.1176/appi.ajp.20230172 | url = https://cdr.lib.unc.edu/downloads/37720q20d| quote = We now have molecular-level details regarding how psychedelic drugs interact with and activate 5-HT2A receptors (39) (Figure 2B). Studies on a related serotonin receptor (5-HT2B) have clarified how LSD can stabilize distinct signaling complexes (40, 41). A key finding of these studies was the discovery that once LSD binds to the 5-HT2A receptor, a lid is formed over the binding pocket, which “traps” LSD for several hours (39, 40) (Figure 2B). These findings imply that at least part of the reason for the long duration of action of drugs like LSD is the trapping of the receptor via conformational changes that occur after drug binding. These studies also showed that this prolonged action of LSD is due in part to a specific residue within the binding pocket, which is found in humans but not in mice or rats (39). This residue (Ser242) also is essential for the high-affinity interactions of LSD, psilocybin, and perhaps other such drugs at the human and nonhuman primate 5-HT2A receptors.}}</ref><ref name="Chen_2017" /> A crystal structure of the serotonin 5-HT<sub>2B</sub> receptor bound to LSD reveals an extracellular loop that forms a "lid" over the diethylamide end of the binding cavity and "traps" LSD in the binding pocket, which explains the slow rate of LSD unbinding from serotonin receptors.<ref name="RothGumpper2023" /><ref name="WackerWang2017">{{cite journal | vauthors = Wacker D, Wang S, McCorvy JD, Betz RM, Venkatakrishnan AJ, Levit A, Lansu K, Schools ZL, Che T, Nichols DE, Shoichet BK, Dror RO, Roth BL | title = Crystal Structure of an LSD-Bound Human Serotonin Receptor | journal = Cell | volume = 168 | issue = 3 | pages = 377–389.e12 | date = January 2017 | pmid = 28129538 | pmc = 5289311 | doi = 10.1016/j.cell.2016.12.033 }}</ref> The related [[lysergamide]] [[lysergic acid amide]] (LSA) that lacks the diethylamide [[Moiety (chemistry)|moiety]] is far less hallucinogenic in comparison.<ref name="WackerWang2017" /> Moreover, a specific residue in the binding pocket is partially responsible for the prolonged action of LSD, and this residue is found in the human protein but not in the receptors of rodents.<ref name="RothGumpper2023" />

LSD is an extraordinarily [[potency (pharmacology)|potent]] [[psychoactive drug]] and is among the most potent psychedelics known in humans.<ref name="Nichols2018a" /><ref name="Nichols2018b" /> It is unclear why LSD is so potent.<ref name="Nichols2018b" /><ref name="Nichols2001">{{cite journal | vauthors = [[David E. Nichols|Nichols DE]] | title = LSD and Its Lysergamide Cousins | pages = 80–87 | journal = The Heffter Review of Psychedelic Research | volume = 2 | date = 2001 | publisher = [[Heffter Research Institute]] | issn = 1534-9640 | url = https://www.heffter.org/wp-content/uploads/2020/04/chap6.pdf | quote = Indeed, the potency of LSD at the 5-HT2A receptor is not as great as that of some of the amphetamine hallucinogens such as DOB or DOI, yet its human potency is about ten times greater. [...] Furthermore, there is a cavity within these receptors that accommodates and is complementary to the activating drug, in this case LSD. What we are forced to conclude is that the area within the receptor that binds to the diethylamide function of LSD is a specific region that must be just large enough to contain the diethyl groups. [...]}}</ref> The [[affinity (pharmacology)|affinity]] and [[receptor activation|activational]] potency of LSD at the human serotonin 5-HT<sub>2A</sub> receptor ''[[in vitro]]'' is unremarkable compared to other psychedelics such as [[DOI (drug)|DOI]] and [[DOB (drug)|DOB]].<ref name="Nichols2018b" /><ref name="Nichols2001" /> It appears that the ''N'',''N''-diethylamide [[moiety (chemistry)|moiety]] of LSD fits into a sterically constrained region of the serotonin 5-HT<sub>2A</sub> receptor that specifically accommodates this moiety.<ref name="Nichols2018b" /><ref name="GumpperNichols2024" /><ref name="Nichols2001" />

LSD, like other psychedelics, has been found to increase the [[gene expression|expression]] of [[gene]]s related to [[synaptic plasticity]] and hence to have [[psychoplastogen]]ic effects.<ref>{{cite journal | vauthors = Calder AE, Hasler G | title = Towards an understanding of psychedelic-induced neuroplasticity | journal = Neuropsychopharmacology | volume = 48 | issue = 1 | pages = 104–112 | date = January 2023 | pmid = 36123427 | pmc = 9700802 | doi = 10.1038/s41386-022-01389-z }}</ref> This is in part due to binding to [[brain-derived neurotrophic factor]] (BDNF) receptor [[tropomyosin receptor kinase B]] (TrkB).<ref>{{cite journal | vauthors = Moliner R, Girych M, Brunello CA, Kovaleva V, Biojone C, Enkavi G, Antenucci L, Kot EF, Goncharuk SA, Kaurinkoski K, Kuutti M, Fred SM, Elsilä LV, Sakson S, Cannarozzo C, Diniz CR, Seiffert N, Rubiolo A, Haapaniemi H, Meshi E, Nagaeva E, Öhman T, Róg T, Kankuri E, Vilar M, Varjosalo M, Korpi ER, Permi P, Mineev KS, Saarma M, Vattulainen I, Casarotto PC, Castrén E | title = Psychedelics promote plasticity by directly binding to BDNF receptor TrkB | journal = Nature Neuroscience | volume = 26 | issue = 6 | pages = 1032–1041 | date = June 2023 | pmid = 37280397 | doi = 10.1038/s41593-023-01316-5 | pmc = 10244169 }}</ref>

There appears to be no significant acute [[drug tolerance|tolerance]] to the subjective effects of LSD.<ref name="Liechti2016">{{citation | author = Matthias Liechti | title = Pharmacology of novel psychoactive substances, MDMA, and LSD | work = Department of Biomedicine. Report 2014–2016 | pages=52–53 | date=2016 | url = https://biomedizin.unibas.ch/fileadmin/user_upload/biomedizin/research/fg_liechti_psychopharmacology_research/DBM_Report_2014-2016_liechti.pdf | quote = LSD produced subjective drug effects that lasted up to 12h (Fig. 3a) and correlated well with the concentrations of LSD in the blood plasma over time (Fig. 3b and c). The half-life of LSD in plasma was 3.5 h. In contrast to LSD, the half-life of MDMA is longer (8h) but the effects of MDMA last only up to 6h despite the continued presence of the substance in the body (Fig. 3d). Thus, there is marked acute tolerance to the effects of MDMA. [...] Fig. 3: Pharmacokinetics-Pharmacodynamics of LSD. LSD effects last up to 12h (a) corresponding to its plasma-concentration time curve (b) and exhibiting no hysteresis in the LSD concentration-effect plot (c). In contrast, the MDMA concentration-effect plot shows pronounced hysteresis consistent with acute tolerance (d).}}</ref> Hence, its [[duration of action|duration]] appears to be dictated by [[pharmacokinetics]] rather than by [[pharmacodynamics]].<ref name="Liechti2016" /> This is in contrast to [[MDMA]], which shows marked acute tolerance and a duration of effects that is shorter than its [[elimination half-life]].<ref name="Liechti2016" />

The [[cryo-EM]] [[protein–ligand complex|structure]]s of the serotonin 5-HT<sub>2A</sub> receptor with LSD, as well as with various other psychedelics and serotonin 5-HT<sub>2A</sub> receptor agonists, have been solved and published by [[Bryan L. Roth]] and colleagues.<ref name="GumpperJainKim2025">{{cite journal | vauthors = Gumpper RH, Jain MK, Kim K, Sun R, Sun N, Xu Z, DiBerto JF, Krumm BE, Kapolka NJ, Kaniskan HÜ, Nichols DE, Jin J, Fay JF, Roth BL | title = The structural diversity of psychedelic drug actions revealed | journal = Nature Communications | volume = 16 | issue = 1 | pages = 2734 | date = March 2025 | pmid = 40108183 | doi = 10.1038/s41467-025-57956-7 | pmc = 11923220 | bibcode = 2025NatCo..16.2734G }}</ref><ref name="GumpperDiBertoJain2022">{{cite conference | vauthors = Gumpper RH, DiBerto J, Jain M, Kim K, Fay J, Roth BL | title = Structures of Hallucinogenic and Non-Hallucinogenic Analogues of the 5-HT2A Receptor Reveals Molecular Insights into Signaling Bias | conference = University of North Carolina at Chapel Hill Department of Pharmacology Research Retreat September 16th, 2022 – William and Ida Friday Center | date = September 2022 | url = https://www.med.unc.edu/pharm/wp-content/uploads/sites/930/2022/07/COMPLETE-PHARM-RETREAT-PROGRAM-2022-UPDATE.pdf#page=37}}</ref>

====Mechanisms of action====
{{Multiple image
| align = left
| total_width = 500
| image1 = FMRI V1 RSFC LSD.png
| caption1 = [[Resting state fMRI]] [[BOLD-contrast imaging]] shows increased [[primary visual cortex]] (V1) [[cerebral blood flow]] (CBF) and increased V1 [[resting state functional connectivity]] (RSFC), which correlated more strongly with the visual hallucinatory aspect of the LSD experience. Increased V1 RSFC also correlated with [[visual analogue scale]] (VAS) ratings of simple hallucinations and the magnitude of CBF observed in the visual cortex correlated positively with ratings of complex imagery on the LSD-induced [[altered state of consciousness]] (ASC).<ref name="pmid27071089">{{cite journal |vauthors=Carhart-Harris RL, Muthukumaraswamy S, Roseman L, Kaelen M, Droog W, Murphy K, Tagliazucchi E, Schenberg EE, Nest T, Orban C, Leech R, Williams LT, Williams TM, Bolstridge M, Sessa B, McGonigle J, Sereno MI, Nichols D, Hellyer PJ, Hobden P, Evans J, Singh KD, Wise RG, Curran HV, Feilding A, Nutt DJ |title=Neural correlates of the LSD experience revealed by multimodal neuroimaging |journal=[[Proceedings of the National Academy of Sciences of the United States of America]] |volume=113 |issue=17 |pages=4853–4858 |date=11 April 2016 |pmid=27071089 |pmc=4855588 |doi=10.1073/pnas.1518377113 |bibcode=2016PNAS..113.4853C |doi-access=free}}</ref>
| width1 = 
| height1 = 
| image2 = FMRI PH RSFC LSD.png
| caption2 = [[Resting state fMRI]] [[BOLD-contrast imaging]] shows decreased [[Parahippocampal gyrus|bilateral parahippocampal]] (PH) [[resting state functional connectivity]] (RSFC), which correlated with the [[ego-dissolution]] aspect of the LSD experience. A significant relationship was also found between decreased [[posterior cingulate cortex]] (PCC) [[Alpha wave|alpha power]] and [[default mode network]] (DMN) disintegration with ego-dissolution.<ref name="pmid27071089" />
| width2 = 
| height2 = 
| footer = 
}}

Neuroimaging studies using [[resting state]] [[fMRI]] recently suggested that LSD changes the cortical functional architecture.<ref name="Singleton SP">{{cite journal | vauthors = Singleton SP, Luppi AI, Carhart-Harris RL, Cruzat J, Roseman L, Nutt DJ, Deco G, Kringelbach ML, Stamatakis EA, Kuceyeski A |title = Receptor-informed network control theory links LSD and psilocybin to a flattening of the brain's control energy landscape|journal = Nat Commun |volume=13 | issue=1 | page=5812 | date=Oct 2022 | pmid=36192411 | doi = 10.1038/s41467-022-33578-1 | pmc=9530221 | bibcode=2022NatCo..13.5812S | doi-access=free }}</ref> These modifications spatially overlap with the distribution of serotoninergic receptors. In particular, increased connectivity and activity were observed in regions with high expression of [[5-HT2A receptor|5-HT<sub>2A</sub>]] receptor, while a decrease in activity and connectivity was observed in cortical areas that are dense with [[5-HT1A receptor|5-HT<sub>1A</sub>]] receptor.<ref name="Delli Pizzi S BP:CNNI">{{cite journal |vauthors=Delli Pizzi S, Chiacchiaretta P, Sestieri C, Ferretti A, Onofrj M, Della Penna S, Roseman L, Timmermann C, Nutt DJ, Carhart-Harris RL, Sensi SL |title=Spatial Correspondence of LSD-Induced Variations on Brain Functioning at Rest With Serotonin Receptor Expression |journal=Biol Psychiatry Cogn Neurosci Neuroimaging |volume=8 |issue=7 |pages=768–776 |date=July 2023 |pmid=37003409 |doi=10.1016/j.bpsc.2023.03.009 |s2cid=257862535}}</ref> Experimental data suggest that subcortical structures, particularly the thalamus, play a synergistic role with the cerebral cortex in mediating the psychedelic experience. LSD, through its binding to cortical [[5-HT2A receptor|5-HT<sub>2A</sub>]] receptor, may enhance excitatory neurotransmission along frontostriatal projections and, consequently, reduce thalamic filtering of sensory stimuli towards the cortex.<ref name="Delli Pizzi S NeuroImage">{{cite journal |vauthors=Delli Pizzi S, Chiacchiaretta P, Sestieri C, Ferretti A, Tullo MG, Della Penna S, Martinotti G, Onofrj M, Roseman L, Timmermann C, Nutt DJ, Carhart-Harris RL, Sensi SL |title=LSD-induced changes in the functional connectivity of distinct thalamic nuclei |journal=NeuroImage |volume=283 |page=120414 |date=Dec 2023 |pmid=37858906 |doi=10.1016/j.neuroimage.2023.120414 |doi-access=free}}</ref> This phenomenon appears to selectively involve ventral, intralaminar, and pulvinar nuclei.<ref name="Delli Pizzi S NeuroImage"/>

===Pharmacokinetics===
The acute effects of LSD normally last between 6 and 12{{nbsp}}hours depending on dosage, tolerance, and age.<ref name="tihkal">{{cite book |vauthors=Shulgin A, Shulgin A |author-link1=Alexander Shulgin |author-link2=Ann Shulgin |chapter-url=http://www.erowid.org/library/books_online/tihkal/tihkal26.shtml |archive-date=15 October 2008 |archive-url=http://archive.wikiwix.com/cache/20081015082653/http://www.erowid.org/library/books_online/tihkal/tihkal26.shtml |chapter=LSD |title=[[TiHKAL]] |location=Berkeley, CA |publisher=Transform Press |date=1997 |isbn=0-9630096-9-9}}</ref><ref name="PassieHalpernStrichtenoth2008" /> Aghajanian and Bing (1964) found LSD had an elimination half-life of only 175&nbsp;minutes (about 3&nbsp;hours);<ref name="Aghajanian">{{cite journal |vauthors=Aghajanian GK, Bing OH |title=Persistence of lysergic acid diethylamide in the plasma of human subjects |journal=Clinical Pharmacology and Therapeutics |volume=5 |issue=5 |pages=611–614 |year=1964 |pmid=14209776 |doi=10.1002/cpt196455611| url=http://www.maps.org/w3pb/new/1964/1964_aghajanian_2224_1.pdf |s2cid=29438767 |archive-url= https://web.archive.org/web/20090327144227/http://www.maps.org/w3pb/new/1964/1964_aghajanian_2224_1.pdf |archive-date=March 27, 2009}}</ref> however, using more accurate techniques, Papac and Foltz (1990) reported that 1&nbsp;μg/kg oral LSD given to a single male volunteer had an apparent plasma half-life of 5.1&nbsp;hours, with a peak plasma concentration of 5&nbsp;ng/mL at 3&nbsp;hours post-dose.<ref name="Papac">{{cite journal |vauthors=Papac DI, Foltz RL |title=Measurement of lysergic acid diethylamide (LSD) in human plasma by gas chromatography/negative ion chemical ionization mass spectrometry |journal=Journal of Analytical Toxicology |volume=14 |issue=3 |pages=189–190 |date=May–June 1990 |pmid=2374410 |doi=10.1093/jat/14.3.189 |url=http://www.erowid.org/references/refs_view.php?A=ShowDocPartFrame&C=ref&ID=6265&DocPartID=6624 |url-status=live|format=PDF |archive-date=April 29, 2011|archive-url=https://web.archive.org/web/20110429060433/http://www.erowid.org/references/refs_view.php?A=ShowDocPartFrame&C=ref&ID=6265&DocPartID=6624}}</ref>

The [[pharmacokinetics]] of LSD were not properly determined until 2015, which is not surprising for a drug with the kind of low-μg potency that LSD possesses.<ref name=Dol2015 /><ref name=Muc2016 /> In a sample of 16 healthy subjects, a single mid-range 200&nbsp;μg oral dose of LSD was found to produce mean [[Cmax (pharmacology)|maximal concentration]]s of 4.5&nbsp;ng/mL at a median of 1.5&nbsp;hours (range 0.5–4&nbsp;hours) post-administration.<ref name=Dol2015 /><ref name=Muc2016 /> Concentrations of LSD decreased following [[first-order kinetics]] with a [[half-life]] of 3.6±0.9 hours and a [[terminal half-life]] of 8.9±5.9 hours.<ref name=Dol2015 /><ref name=Muc2016 />

The effects of the dose of LSD given lasted for up to 12&nbsp;hours and were closely correlated with the concentrations of LSD present in circulation over time, with no acute [[drug tolerance|tolerance]] observed.<ref name="Dol2015" /><ref name="Muc2016" /> Only 1% of the drug was eliminated in [[urine]] unchanged, whereas 13% was eliminated as the major [[metabolite]] 2-oxo-3-hydroxy-LSD (O-H-LSD) within 24&nbsp;hours.<ref name="Dol2015" /><ref name="Muc2016" /> O-H-LSD is formed by [[cytochrome P450]] [[enzyme]]s, although the specific enzymes involved are unknown, and it does not appear to be known whether O-H-LSD is pharmacologically active or not.<ref name="Dol2015" /><ref name="Muc2016" /> The oral [[bioavailability]] of LSD was crudely estimated as approximately 71% using previous data on [[intravenous]] administration of LSD.<ref name="Dol2015" /><ref name="Muc2016" /> The sample was equally divided between male and female subjects and there were no significant sex differences observed in the pharmacokinetics of LSD.<ref name="Dol2015" /><ref name="Muc2016" /> In a subsequent, higher-quality study, the oral bioavailability of LSD was about 80%.<ref name="Holze_2024">{{cite journal | vauthors = Holze F, Mueller L, Vizeli P, Luethi D, Rudin D, Hysek C, Liechti M, Arikci D | title = Oral LSD base and tartrate bioequivalence and absolute bioavailability in healthy participants | journal = Neuroscience Applied | volume = 3 | pages = 105132 | date = 2024 | doi = 10.1016/j.nsa.2024.105132 | doi-access = free }}</ref>

A large meal before taking LSD has been found to result in circulating levels that were 50% lower than on an empty stomach.<ref name="PassieHalpernStrichtenoth2008" />

It has been said that there is a peculiar 40-minute lag before [[onset of action|onset]] of the psychedelic effects of LSD when it is administered [[intravenous injection|intravenously]].<ref name="GumpperNichols2024" /> This has been said to be related to time-dependent interactions of LSD with the serotonin 5-HT<sub>2A</sub> receptor.<ref name="GumpperNichols2024" /> However, contradicting the preceding claims, other sources have stated that intravenous injection of LSD results in onset of effects within a few minutes.<ref name="PassieHalpernStrichtenoth2008" /><ref name="Shulgin1980b" /> In addition, [[intrathecal injection]] (intraspinal injection) is reported to have a virtually instantaneous onset of action.<ref name="PassieHalpernStrichtenoth2008" /><ref name="Shulgin1980b" /> Doses of LSD are said to be similar by oral and injectable routes, with the exception of intrathecal injection in which the dosage is reduced to about one-third of usual.<ref name="Shulgin1980b" />