LSZ

{{Short description|Psychedelic drug}} {{Other uses}} {{Infobox drug | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 452018128 | drug_name = LSZ | image = LA-SS-Az structure.svg | image_class = skin-invert-image | width = 175px | caption = Structure of LA-SS-Az (''trans''-(''S'',''S'')-LSZ), the most active and commonly used isomer of LSZ | image2 = LSZ 3D.png | image_class2 = bg-transparent | width2 = 225px | caption2 = Ball-and-stick model of LSZ

<!-- Clinical data --> | tradename = | dependency_liability = | routes_of_administration = Oral<ref name="HalberstadtChathaKlein2020" /><ref name="MallaroniMasonVinckenbosch2022" /> | class = Non-selective serotonin receptor agonist; Serotonin 5-HT_2A receptor agonist; Serotonergic psychedelic; Hallucinogen

<!-- Legal status --> | legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --> | legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII --> | legal_DE = NpSG | legal_UK = Class A | legal_US = | legal_status = Illegal in Denmark, France,<ref name="LegiFrance">{{cite web|date=20 May 2021|title=Arrêté du 20 mai 2021 modifiant l'arrêté du 22 février 1990 fixant la liste des substances classées comme stupéfiants|url=https://www.legifrance.gouv.fr/jorf/id/JORFTEXT000043523554|website=www.legifrance.gouv.fr|language=fr}}</ref> Sweden, and Switzerland

<!-- Pharmacokinetic data --> | bioavailability = | protein_bound = | metabolism = | onset = | elimination_half-life = | duration_of_action = 3–11 hours (median 8 hours)<ref name="MallaroniMasonVinckenbosch2022" /> | excretion =

<!-- Identifiers --> | index_comment = (''S'',''S'')-isomer, freebase | index2_comment = (''S'',''S'')-isomer, tartrate salt | index_label = freebase | index2_label = tartrate salt | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 470666-31-0 | CAS_number2_Ref = {{cascite|changed|??}} | CAS_number2= 470666-32-1 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 8SWJ525W4R | PubChem = 71301249 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 30773535 | DrugBank = DB15196 | ChEMBL = | synonyms = Lysergic acid 2,4-dimethylazetidine; Lysergic acid 2''S'',4''S''-dimethylazetidine; LSZ; LA-Azetidide; LSD-Azetidide; LA-SS-Az; SS-LSZ; (''S'',''S'')-LSZ; Diazedine; λ; Lambda

<!-- Chemical data --> | IUPAC_name = [(6a''R'',9''R'')-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-yl]-[(2''S'',4''S'')-2,4-dimethylazetidin-1-yl]methanone | C=21 | H=25 | N=3 | O=1 | SMILES = C[C@H]1C[C@@H](N1C(=O)[C@H]2CN([C@@H]3CC4=CNC5=CC=CC(=C45)C3=C2)C)C | StdInChI_Ref = {{stdinchicite|changed|chemspider}} | StdInChI = 1S/C21H25N3O/c1-12-7-13(2)24(12)21(25)15-8-17-16-5-4-6-18-20(16)14(10-22-18)9-19(17)23(3)11-15/h4-6,8,10,12-13,15,19,22H,7,9,11H2,1-3H3/t12-,13-,15+,19+/m0/s1 | StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} | StdInChIKey = DUKNIHFTDAXJON-CTQRGLTFSA-N }}

'''LSZ''', also known as '''lysergic acid 2,4-dimethylazetidide''' or as '''LA-Azetidide''' ('''LA-Az'''), is a psychedelic drug of the lysergamide family related to lysergic acid diethylamide (LSD).<ref name="Nichols2018a" /><ref name="Nichols2018b" /><ref name="BrandtKavanaghWestphal2017" /><ref name="NicholsFrescasMarona-Lewicka2002" /> It is taken orally.<ref name="HalberstadtChathaKlein2020" /><ref name="MallaroniMasonVinckenbosch2022" />

The drug acts as a non-selective serotonin receptor agonist, including of the serotonin 5-HT_2A receptor.<ref name="Nichols2018a" /><ref name="NicholsFrescasMarona-Lewicka2002" /> It also interacts with dopamine receptors.<ref name="NicholsFrescasMarona-Lewicka2002" /><ref name="Braden2008" /> The compound is a close analogue of LSD that has been modified at the amide to be more rigid and to have three diastereomers.<ref name="Nichols2018a" /><ref name="BrandtKavanaghWestphal2017" /><ref name="NicholsFrescasMarona-Lewicka2002" /> '''LA-SS-Az''', the (''S'',''S'')- isomer, is the most potent and similar isomer to LSD, and is the typically employed form of LSZ.<ref name="Nichols2018b" /><ref name="BrandtKavanaghWestphal2017" /><ref name="NicholsFrescasMarona-Lewicka2002" /> LA-SS-Az and the other isomers of LSZ produce psychedelic-like effects in animals.<ref name="NicholsFrescasMarona-Lewicka2002" /><ref name="BrandtKavanaghWestphal2017" />

LSZ was first described in the scientific literature by David E. Nichols and colleagues in 2002.<ref name="BrandtKavanaghWestphal2017" /><ref name="NicholsFrescasMarona-Lewicka2002" /> It was developed as a tool for studying psychedelic interactions with the serotonin 5-HT_2A receptor and followed the earlier unstable compound LA-Aziridine developed by Nichols and Robert Oberlender.<ref name="Nichols2018a" /><ref name="NicholsFrescasMarona-Lewicka2002" /><ref name="PfaffHuangMarona-Lewicka1994" /><ref name="NicholsMonteHuang1996" /><ref name="Oberlender1989" /> LSZ, under the name "diazedine", may have been produced on a small scale by the LSD manufacturers William Leonard Pickard and Gordon Todd Skinner around the year 2000.<ref name="Morris2011a" /><ref name="Morris2011b" /><ref name="Morris2011-S0E5" /> It was first definitely encountered as a novel designer drug in 2013 and then became a popular psychedelic.<ref name="BrandtKavanaghWestphal2017" /><ref name="EMCDDA2014" /><ref name="BrandtKavanaghWestphal2020" /><ref name="MallaroniMasonVinckenbosch2022" /> LSZ is a controlled substance in several European countries.<ref name="DerBundesrat2015" /><ref name="Lægemiddelstyrelsen2015" /><ref name="Folkhälsomyndigheten2015" /><ref name="ACMD2014" />

==Use and effects== LSZ, as the (''S'',''S'')- isomer LA-SS-Az, has been reported to have a dose range of 100 to 200{{nbsp}}μg or 100 to 300{{nbsp}}μg orally, with a typical dose estimate of 150 or 200{{nbsp}}μg.<ref name="HalberstadtChathaKlein2020" /><ref name="MallaroniMasonVinckenbosch2022">{{cite journal | vauthors = Mallaroni P, Mason NL, Vinckenbosch FR, Ramaekers JG | title = The use patterns of novel psychedelics: experiential fingerprints of substituted phenethylamines, tryptamines and lysergamides | journal = Psychopharmacology (Berl) | volume = 239 | issue = 6 | pages = 1783–1796 | date = June 2022 | pmid = 35487983 | pmc = 9166850 | doi = 10.1007/s00213-022-06142-4 | url = }}</ref><ref name="BrandtKavanaghWestphal2017" /> This dose range is notably higher than that of LSD, which is 50 to 200{{nbsp}}μg with a typical dose of about 100{{nbsp}}μg.<ref name="LiechtiHolze2022">{{cite book | vauthors = Liechti ME, Holze F | title = Disruptive Psychopharmacology | chapter = Dosing Psychedelics and MDMA | series = Curr Top Behav Neurosci | volume = 56 | pages = 3–21 | date = 2022 | pmid = 34734392 | doi = 10.1007/7854_2021_270 | isbn = 978-3-031-12183-8 | chapter-url = https://www.researchgate.net/publication/355943062}}</ref><ref name="TiHKAL-LSD">{{cite book | author1 = Alexander T. Shulgin | author2 = Ann Shulgin | chapter = #26. LSD-25 Acid; Lysergide; D-Lysergic Acid Diethylamide; Meth-LAD; D-Lysergamide, N,N-Diethyl; N,N-Diethyl-D-Lysergamide; 9,10-Didehydro-N,N-Diethyl-6-Methylergoline-8b-Carboxamide | pages = 490–499 | chapter-url = https://www.erowid.org/library/books_online/tihkal/tihkal26.shtml | title = TiHKAL: The Continuation | publisher = Transform Press | date = 1997 | edition = 1st | location = Berkeley, CA | isbn = 978-0-9630096-9-2 | oclc = 38503252}}</ref><ref name="Shulgin2003">{{cite book | vauthors = Shulgin AT | chapter=Basic Pharmacology and Effects | pages=67–137 | veditors = Laing RR | title=Hallucinogens: A Forensic Drug Handbook | publisher=Elsevier Science | series=Forensic Drug Handbook Series | year=2003 | isbn=978-0-12-433951-4 | url=https://books.google.com/books?id=l1DrqgobbcwC | chapter-url=https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=6bb3a7499da8e9852b39cd4db16891147c83f5c6 | access-date=1 February 2025}}</ref><ref name="JacobShulgin1994">{{cite journal | vauthors = Jacob P, Shulgin AT | title = Structure-activity relationships of the classic hallucinogens and their analogs | journal = NIDA Res Monogr | volume = 146 | issue = | pages = 74–91 | date = 1994 | pmid = 8742795 | doi = | url = https://archives.nida.nih.gov/sites/default/files/monograph146.pdf#page=79 | archive-url = https://web.archive.org/web/20230805004551/https://archives.nida.nih.gov/sites/default/files/monograph146.pdf#page=79 | url-status = dead | archive-date = August 5, 2023}}</ref><ref name="HalberstadtChathaKlein2020">{{cite journal | vauthors = Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD | title = Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species | journal = Neuropharmacology | volume = 167 | issue = | article-number = 107933 | date = May 2020 | pmid = 31917152 | pmc = 9191653 | doi = 10.1016/j.neuropharm.2019.107933 | url = http://usdbiology.com/cliff/Courses/Advanced%20Seminars%20in%20Neuroendocrinology/Serotonergic%20Psychedelics%2020/Halberstadt%2020%20Neuropharm%20potency%20of%20hallucinogens%20%20head-twitch.pdf | quote = Table 4 Human potency data for selected hallucinogens. [...] }}</ref> According to David E. Nichols however, LSZ is approximately equipotent with LSD based on human anecdotal reports.<ref name="Nichols2018b">{{cite journal | vauthors = Nichols DE | title = Dark Classics in Chemical Neuroscience: Lysergic Acid Diethylamide (LSD) | journal = ACS Chemical Neuroscience | volume = 9 | issue = 10 | pages = 2331–2343 | date = October 2018 | pmid = 29461039 | url = https://shaunlacob.com/wp-content/uploads/2020/12/DC-LSD.pdf | doi = 10.1021/acschemneuro.8b00043 | quote = One analogue of LSD modified in the amide moiety has been reported to have human activity approximately equipotent to LSD. The lysergamide of 2S,4S-dimethylazetidine52 has been sold as “LSZ” and anecdotal reports of its human activity have appeared. Interestingly, the crystal structure of LSD bound within the human serotonin 5-HT2B receptor was recently reported.78 The conformation of the LSD molecule within the crystal structure was essentially superimposable on the structure of the lysergamide of 2S,4S-dimethylazetidine.52}}</ref> The duration of LSZ is reported to be in the range of 3 to 11{{nbsp}}hours, with a median duration of around 8{{nbsp}}hours.<ref name="MallaroniMasonVinckenbosch2022" /> This was shorter than the duration of the LSD prodrug 1P-LSD, which had a duration range of 6 to 14{{nbsp}}hours and a median duration of about 10{{nbsp}}hours in the same study.<ref name="MallaroniMasonVinckenbosch2022" /> The detailed effects of LSZ, aside from it being a psychedelic similarly to LSD, do not appear to have been reported in the published literature.<ref name="HalberstadtChathaKlein2020" /><ref name="MallaroniMasonVinckenbosch2022" /><ref name="Nichols2018a" />

==Interactions== {{See also|Psychedelic drug#Interactions|Trip killer#Serotonergic psychedelic antidotes}}

==Pharmacology== ===Pharmacodynamics=== {| class="wikitable floatleft" style="font-size:small;" |+ {{Nowrap|LSZ activities}} |- ! Target !! Affinity (K_i, nM) |- | 5-HT_1A || 0.45 |- | 5-HT_1B || 2.4 |- | 5-HT_1D || 2.4 |- | 5-HT_1E || 276 |- | 5-HT_1F || {{Abbr|ND|No data}} |- | 5-HT_2A || 0.54–19.2 (K_i)<br />0.32–957 ({{Abbrlink|EC₅₀|half-maximal effective concentration}})<br />56–85% ({{Abbrlink|E_max|maximal efficacy}}) |- | 5-HT_2B || 27 (K_i)<br />0.4–58.4 ({{Abbr|EC₅₀|half-maximal effective concentration}})<br />57–74% ({{Abbr|E_max|maximal efficacy}}) |- | 5-HT_2C || 37 (K_i)<br />992 ({{Abbr|EC₅₀|half-maximal effective concentration}})<br />39% ({{Abbr|E_max|maximal efficacy}}) |- | 5-HT₃ || >10,000 |- | 5-HT₄ || {{Abbr|ND|No data}} |- | 5-HT_5A || 27.3 |- | 5-HT₆ || 14.5 |- | 5-HT₇ || 14.3 |- | α_1A || 850.2 |- | α_1B || >10,000 |- | α_1D–α_2C || {{Abbr|ND|No data}} |- | β₁ || 75.8 |- | β₂ || 1,069 |- | β₃ || {{Abbr|ND|No data}} |- | D₁ || 292 |- | D₂ || 73.6–110 |- | D₃ || 6.0 |- | D₄ || 36–95.5 |- | D₅ || 402.2 |- | H₁ || 2,504 |- | H₂–H₄ || {{Abbr|ND|No data}} |- | M₁–M₅ || {{Abbr|ND|No data}} |- | I₁ || {{Abbr|ND|No data}} |- | σ₁, σ₂ || {{Abbr|ND|No data}} |- | {{Abbrlink|TAAR1|Trace amine-associated receptor 1}} || {{Abbr|ND|No data}} |- | {{Abbrlink|SERT|Serotonin transporter}} || >10,000 (K_i) |- | {{Abbrlink|NET|Norepinephrine transporter}} || >10,000 (K_i) |- | {{Abbrlink|DAT|Dopamine transporter}} || >10,000 (K_i) |- class="sortbottom" | colspan="2" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | '''Notes:''' The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. '''Refs:''' <ref name="PDSPKiDatabase">{{cite web | title=Kᵢ Database | website=PDSP | date=1 April 2025 | url=https://pdsp.unc.edu/kidb2/kidb/web/kis-results/index?KisResultsSearch%5Binput_receptors%5D=&KisResultsSearch%5Binput_sources%5D=&KisResultsSearch%5Binput_species%5D=&KisResultsSearch%5Binput_hot_ligands%5D=&KisResultsSearch%5Binput_test_ligands%5D=&KisResultsSearch%5Binput_test_ligands%5D%5B%5D=2908&KisResultsSearch%5Binput_citations%5D=&KisResultsSearch%5BsearchType%5D=&KisResultsSearch%5Bki_val_from%5D=&KisResultsSearch%5Bki_val_to%5D=&KisResultsSearch%5Bcustom_ki_val%5D= | access-date=1 April 2025}}</ref><ref name="BindingDB">{{cite web | last=Liu | first=Tiqing | title=BindingDB BDBM50118576 (2,4-Dimethyl-azetidin-1-yl)-(7-methyl-4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinolin-9-yl)-methanone::CHEMBL137781 | website=BindingDB | url=https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50118576 | access-date=1 April 2025}}</ref><ref name="Ray2010">{{cite journal | vauthors = Ray TS | title = Psychedelics and the human receptorome | journal = PLOS ONE | volume = 5 | issue = 2 |article-number=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="NicholsFrescasMarona-Lewicka2002">{{cite journal | vauthors = Nichols DE, Frescas S, Marona-Lewicka D, Kurrasch-Orbaugh DM | title = Lysergamides of isomeric 2,4-dimethylazetidines map the binding orientation of the diethylamide moiety in the potent hallucinogenic agent N,N-diethyllysergamide (LSD) | journal = J Med Chem | volume = 45 | issue = 19 | pages = 4344–4349 | date = September 2002 | pmid = 12213075 | doi = 10.1021/jm020153s | url = }}</ref><ref name="Braden2008">{{cite thesis | last=Braden | first=Michael Robert | name-list-style = vanc | degree = Ph.D. | title=Towards a biophysical understanding of hallucinogen action | publisher = Purdue University | date = 2007 | id = {{ProQuest|304838368}} | url=https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=9a30faca37ad48466b87a192ccd542401dc24012}}</ref><ref name="McCorvy2013">{{cite web | 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 | website=Purdue e-Pubs | date=16 January 2013 | url=https://docs.lib.purdue.edu/dissertations/AAI3545320/ | archive-date=26 March 2025 | archive-url=https://web.archive.org/web/20250326000000/https://docs.lib.purdue.edu/dissertations/AAI3545320/}} [https://bitnest.netfirms.com/external/Theses/McCorvey2012 Alt 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 | pmc = 5289311 | doi = 10.1016/j.cell.2016.12.033 | url = }}</ref><ref name="Nichols2012">{{cite journal | vauthors = Nichols DE | title=Structure–activity relationships of serotonin 5-HT2A agonists | journal=Wiley Interdisciplinary Reviews: Membrane Transport and Signaling | volume=1 | issue=5 | date=2012 | issn=2190-460X | doi=10.1002/wmts.42 | doi-access=free | pages=559–579}}</ref><ref name="Nichols2018a" /> |}

LSZ has been found to bind non-selectively to serotonin, dopamine, and certain other receptors.<ref name="NicholsFrescasMarona-Lewicka2002" /><ref name="Ray2010" /><ref name="Braden2008" /><ref name="McCorvy2013" /> It shows especially high affinity for the serotonin 5-HT_1A, 5-HT_2A, and 5-HT_2C receptors, among others.<ref name="NicholsFrescasMarona-Lewicka2002" /><ref name="Ray2010" /><ref name="Braden2008" /> The drug acts as a potent agonist of the serotonin 5-HT_2A and 5-HT_2C receptors, with potency and efficacy similar to that of LSD.<ref name="NicholsFrescasMarona-Lewicka2002" /><ref name="Braden2008" /><ref name="McCorvy2013" /> It may be more potent than LSD as an agonist of the serotonin 5-HT_1A receptor.<ref name="NicholsFrescasMarona-Lewicka2002" />

LSZ produces the head-twitch response, a behavioral proxy of psychedelic-like effects, in rodents.<ref name="HalberstadtGeyer2018">{{cite book | vauthors = Halberstadt AL, Geyer MA | title = Behavioral Neurobiology of Psychedelic Drugs | chapter = Effect of Hallucinogens on Unconditioned Behavior | series = Curr Top Behav Neurosci | 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 = | quote = Two other lysergamides sold as “research chemicals,” N6 -allyl-6-nor-LSD (AL-LAD) and (2′ S,4′S)-lysergic acid 2,4-dimethylazetidide (LSZ), have also been shown to induce the HTR (Brandt et al. 2017). The potency of LSZ (ED50 = 114 nmol/kg) is approximately the same as LSD, whereas AL-LAD is slightly less potent (ED50 = 175 nmol/kg).}}</ref><ref name="HalberstadtChathaKlein2020" /><ref name="BrandtKavanaghWestphal2017" /> It shows about the same potency as LSD and AL-LAD in producing this effect.<ref name="HalberstadtGeyer2018" /><ref name="HalberstadtChathaKlein2020" /> However, LSZ shows a weaker maximal head-twitch response than LSD or AL-LAD.<ref name="BrandtKavanaghWestphal2017" /> This might be due to lower efficacy at the serotonin 5-HT_2A receptor or stronger actions at other receptors like the serotonin 5-HT_1A or 5-HT_2C receptor.<ref name="BrandtKavanaghWestphal2017" /> LSZ also substitutes for LSD in rodent drug discrimination tests.<ref name="HalberstadtChathaKlein2020" /><ref name="NicholsFrescasMarona-Lewicka2002" /> It was about 1.8-fold more potent than LSD in this assay.<ref name="HalberstadtChathaKlein2020" /><ref name="NicholsFrescasMarona-Lewicka2002" /> All three isomers of LSZ fully substituted for LSD in rodent drug discrimination tests, but the (''S'',''S'')- isomer was the most potent and was the only isomer that was more potent than LSD.<ref name="BrandtKavanaghWestphal2017" /><ref name="NicholsFrescasMarona-Lewicka2002" /> In addition, only the (''S'',''S'') isomer fully substituted for the LSD-like selective serotonin 5-HT_1A receptor full agonist and partial ergoline LY-293284.<ref name="BrandtKavanaghWestphal2017" /><ref name="NicholsFrescasMarona-Lewicka2002" /> In contrast to LSZ, LSD itself does not substitute for LY-293284 in drug discrimination tests.<ref name="NicholsFrescasMarona-Lewicka2002" />

In addition to its psychedelic effects, LSZ has been found to produce anti-inflammatory effects in preclinical research.<ref name="BrandtKavanaghWestphal2017" /><ref name="YuBecnelZerfaoui2008">{{cite journal | vauthors = Yu B, Becnel J, Zerfaoui M, Rohatgi R, Boulares AH, Nichols CD | title = Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency | journal = J Pharmacol Exp Ther | volume = 327 | issue = 2 | pages = 316–323 | date = November 2008 | pmid = 18708586 | doi = 10.1124/jpet.108.143461 | url = }}</ref>

===Pharmacokinetics=== The ''in-vitro'' metabolism of LSZ has been studied.<ref name="WagmannRichterKehl2019">{{cite journal | vauthors = Wagmann L, Richter LH, Kehl T, Wack F, Bergstrand MP, Brandt SD, Stratford A, Maurer HH, Meyer MR | title = In vitro metabolic fate of nine LSD-based new psychoactive substances and their analytical detectability in different urinary screening procedures | journal = Anal Bioanal Chem | volume = 411 | issue = 19 | pages = 4751–4763 | date = July 2019 | pmid = 30617391 | doi = 10.1007/s00216-018-1558-9 | url = }}</ref>

==Chemistry== LSZ, also known as lysergic acid 2,4-dimethylazetidide or as LA-Azetidine (LA-Az), is a substituted lysergamide derivative related to lysergic acid diethylamide (LSD).<ref name="DuanCaoWang2024" /><ref name="BrandtKavanaghWestphal2017" /><ref name="NicholsFrescasMarona-Lewicka2002" /> It is the analogue of LSD in which the ''N'',''N''-diethylamide moiety has been replaced with an 2,4-dimethylazetidine moiety.<ref name="DuanCaoWang2024" /><ref name="BrandtKavanaghWestphal2017" /><ref name="NicholsFrescasMarona-Lewicka2002" /> The compound has three possible diastereomers around the azetidine ring, including the ''cis''-(2''RS'',4''SR'')-, ''trans''-(2''R'',4''R'')-, and ''trans''-(2''S'',4''S'')- 2,4-dimethylazetidine isomers.<ref name="GumpperNichols2024">{{cite journal | vauthors = Gumpper RH, Nichols DE | title = Chemistry/structural biology of psychedelic drugs and their receptor(s) | journal = Br J Pharmacol | volume = | issue = | date = October 2024 | article-number = bph.17361 | pmid = 39354889 | doi = 10.1111/bph.17361 | url = | quote = To gain a better understanding of the diethylamide function, three rigid analogues of LSD were prepared where the diethylamide was replaced by trans-2R,4R-, 2S,4S- and cis-2RS,4SR-dimethylazetidines (Figure 4). Only the 2S,4S-dimethylazetidide had potency nearly comparable to LSD in drug discrimination assays in LSD-trained rats (Nichols et al., 2002). Virtual docking of LSD into a homology model of the 5-HT2A receptor suggested that the diethylamide of LSD might interact with residues in extracellular loop 2 of the 5-HT2A receptor (Juncosa, 2011). [...] When the crystal structure of LSD in the 5-HT2B receptor was subsequently determined, it was observed that only the 2S,4Sdimethylazetine analogue mimicked the conformation of the diethyl groups of LSD (Wacker et al., 2017). This stereoisomer has appeared on the illicit drug market as ‘LSZ’. [...]}}</ref><ref name="BrandtKavanaghWestphal2017" /><ref name="NicholsFrescasMarona-Lewicka2002" /> The (''S'',''S'')- isomer, also known as LA-SS-Az, is the most potent diastereomer and is the typically employed form of the compound.<ref name="BrandtKavanaghWestphal2017" /><ref name="NicholsFrescasMarona-Lewicka2002" />

{{Gallery | title = LSZ and its three diastereomers<ref name="Nichols2012" /><ref name="Nichols2018a" /> | height = 150 | width = 130 | File:LSD-azetidine.svg | class1=skin-invert-image || {{Center|LSZ}} | File:Cis-LSZ structure.svg | class2=skin-invert-image || {{Center|''cis''-LSZ}} | File:Trans-(R,R)-LSZ structure.svg | class3=skin-invert-image | {{Center|''trans''-(''R'',''R'')-LSZ}} | File:LA-SS-Az structure.svg | class4=skin-invert-image | {{Center|''trans''-(''S'',''S'')-LSZ<br />(LA-SS-Az)}} }}

===Synthesis=== The chemical synthesis of LSZ has been described.<ref name="NicholsFrescasMarona-Lewicka2002" />

===Analogues=== Analogues of LSZ include other lysergamides like the 6-substituted lysergamides ETH-LAD, PRO-LAD, AL-LAD, and CE-LAD; the amide-substituted lysergamides LA-3Cl-SB, EcPLA, and MiPLA; the amide-cycilzed lysergamides LA-Aziridine, LA-Pyr (LPD-824), LPN, LA-Pip, LA-Morph (LSM-775), and LA-Azepane; and the ester prodrugs ALD-52 (1A-LSD), 1P-LSD, 1cP-LSD, 1V-LSD, 1B-LSD, 1P-ETH-LAD, and 1cP-AL-LAD, among others.

==History== LSZ was developed by David E. Nichols and colleagues at Purdue University and was first described by them in the scientific literature in 2002.<ref name="BrandtKavanaghWestphal2017">{{cite journal | vauthors = Brandt SD, Kavanagh PV, Westphal F, Elliott SP, Wallach J, Colestock T, Burrow TE, Chapman SJ, Stratford A, Nichols DE, Halberstadt AL | display-authors = 6 | title = Return of the lysergamides. Part II: Analytical and behavioural characterization of N⁶ -allyl-6-norlysergic acid diethylamide (AL-LAD) and (2'S,4'S)-lysergic acid 2,4-dimethylazetidide (LSZ) | journal = Drug Testing and Analysis | volume = 9 | issue = 1 | pages = 38–50 | date = January 2017 | pmid = 27265891 | pmc = 5411264 | doi = 10.1002/dta.1985 | quote = [...] Powdered samples of (2’S,4’S)-lysergic acid 2,4-dimethylazetidide (LSZ) and N6 -allyl-6-norlysergic acid diethylamide (AL-LAD) tartrate were obtained from Synex Ltd (London, UK). Blotters labelled to contain 150 μg AL-LAD and 150 μg LSZ, and blank blotter paper, were provided by the same vendor. [...]}}</ref><ref name="NicholsFrescasMarona-Lewicka2002" /> It was developed to help better understand the binding orientation of LSD at the serotonin 5-HT_2A receptor and to help further map the topography of the receptor.<ref name="BrandtKavanaghWestphal2017" /> LSZ is a rigid analogue of LSD in which the ''N'',''N''-diethylamide moiety has been replaced with and constrained into a 2,4-dimethylazetidine moiety.<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 = | quote = Replacing the diethylamino group of LSD with a conformationally restricted ((2S,4S)-2,4-dimethylazetidinyl group, which has been demonstrated to be able to mimic the active conformation of the diethylamino group bound to the 5- HT2AR,155 afforded compound LSZ (70). Compound LSZ could induce significant HTR effects in mice with an ED50 of 52 μg/kg.163}}</ref><ref name="BrandtKavanaghWestphal2017" /><ref name="NicholsFrescasMarona-Lewicka2002" /> Moreover, the compound has two additional chiral centers due to this modification, with three possible diastereomers.<ref name="BrandtKavanaghWestphal2017" /><ref name="NicholsFrescasMarona-Lewicka2002" />

Nichols and colleagues like Robert Oberlender had initially attempted to do this research by employing the closely related and very similar compound LA-Aziridine in the 1980s, but this drug proved to be highly chemically unstable such that ''in-vivo'' studies were precluded.<ref name="NicholsFrescasMarona-Lewicka2002" /><ref name="PfaffHuangMarona-Lewicka1994">{{cite journal | vauthors = Pfaff RC, Huang X, Marona-Lewicka D, Oberlender R, Nichols DE | title = Lysergamides revisited | journal = NIDA Research Monograph | volume = 146 | pages = 52–73 | date = 1994 | pmid = 8742794 | url = https://archives.nida.nih.gov/sites/default/files/monograph146.pdf#page=57 | archive-url = https://web.archive.org/web/20230805004551/https://archives.nida.nih.gov/sites/default/files/monograph146.pdf#page=57 | url-status = dead | archive-date = August 5, 2023 }}</ref><ref name="NicholsMonteHuang1996">{{cite journal | vauthors = Nichols DE, Monte A, Huang X, Marona-Lewicka D | title = Stereoselective pharmacological effects of lysergic acid amides possessing chirality in the amide substituent | journal = Behavioural Brain Research | volume = 73 | issue = 1–2 | pages = 117–119 | date = 1996 | pmid = 8788487 | doi = 10.1016/0166-4328(96)00080-0 | url = https://chemistry.mdma.ch/hiveboard/rhodium/pdf/nichols/nichols-2-aminobutane-lysergamide.pdf}}</ref><ref name="Oberlender1989">{{cite web | vauthors = Oberlender RA | title = Stereoselective aspects of hallucinogenic drug action and drug discrimination studies of entactogens | date = May 1989 | publisher = Purdue University | website = Purdue e-Pubs | url = https://bitnest.netfirms.com/external/Theses/Oberlender1989}}</ref> With the development of LSZ, the team determined that the (''S'',''S'')- isomer, LA-SS-Az, was the most potent and hence most optimal configuration of LSZ in terms of serotonin 5-HT_2A receptor activation and psychedelic-like effects in animals.<ref name="BrandtKavanaghWestphal2017" /><ref name="NicholsFrescasMarona-Lewicka2002" /> In addition, the conformation of LSD within the crystal structure of the closely related serotonin 5-HT_2B receptor was later found to be essentially superimposable with the structure of LA-SS-Az.<ref name="Nichols2018a" /><ref name="GumpperNichols2024" /><ref name="WackerWangMcCorvy2017"/> Similar findings were made with virtual docking studies with the serotonin 5-HT_2A receptor.<ref name="Nichols2018a">{{cite book | vauthors = Nichols DE | chapter = Chemistry and Structure–Activity Relationships of Psychedelics | title = Behavioral Neurobiology of Psychedelic Drugs | journal = Current Topics in Behavioral Neurosciences | series = Curr Top Behav Neurosci | volume = 36 | issue = | pages = 1–43 | date = 2018 | pmid = 28401524 | doi = 10.1007/7854_2017_475 | isbn = 978-3-662-55878-2 | url = | quote = To test the hypothesis that the receptor might have a region that was optimally complementary to the N,N-diethylamide, the synthesis and testing of conformationally constrained 2,3-dimethylazetidine amides of lysergic acid was carried out (Nichols et al. 2002). These dimethylazetidines exist in three isomeric forms: the 2,3-cis meso isomer 27, the R,R-trans 28, and the S,S-trans 29 isomers. The amide of each of these was prepared from lysergic acid and tested. [...] Virtual docking of LSD, 28, and 29 into an in silico agonist-activated model of the 5-HT2A receptor revealed that the diethyl groups of LSD nestle into a region that is bounded by a number of residues near the extracellular face of the receptor (Juncosa 2011). Further, extracellular loop 2 (EL2) was observed to interact with the diethylamide moiety. In particular, Leu-229 in EL2 was found to be critical for this interaction (McCorvy 2012). The conformation of EL2 was very similar after docking either LSD or S,S-isomer 29, whereas EL2 was significantly displaced (ca. 4 Å at Leu-229) by docking of R,R-28. After docking of LSD, followed by molecular dynamics and minimization, the conformations adopted by the ethyl groups were observed to mirror the configurations in S,S-29. Curiously, the receptor appears to have evolved to be complementary to the diethyl moiety of LSD in a specific conformation.}}</ref><ref name="GumpperNichols2024" /> LSZ, as LA-SS-Az, is among the only known analogues of LSD modified at the amide to have similar or greater psychedelic-type potency.<ref name="Nichols2018a" /><ref name="NicholsFrescasMarona-Lewicka2002" />

According to Krystle Cole in an interview with journalist and researcher Hamilton Morris, the LSD clandestine manufacturers William Leonard Pickard and Gordon Todd Skinner had synthesized and experimented with a psychedelic drug they called "diazedine" around the year 2000.<ref name="Morris2011a">{{cite web|url=https://www.vice.com/en/article/life-is-a-cosmic-giggle-803-v18n5/ |title=Life Is a Cosmic Giggle on the Breath of the Universe | vauthors = Morris H |publisher=Vice Magazine |date=1 May 2011|access-date=2011-06-15 | quote=There were other novel substances as well. Leonard made a new LSD analog called “diazedine,” though I don’t know exactly what that was either. Are you familiar with lysergic acid 2,4-dimethylazetidide?2 No, but they were calling this diazedine. It was also crazy, but nothing earth-shattering. Leonard gave it to Todd in a bottle of Everclear for testing, and we would dose a capful at a time. Apparently, diazedine failed to be doable on a large scale because the production costs were too high and the yields too low. Diazedine caused a lot of stress between Todd and Leonard, because they had high expectations for it as an LSD alternative. [...] 2 Lysergic acid 2,4-dimethylazetidide (aka LSZ) belongs to a very small group of serotonergic psychedelics that surpass LSD in potency. Aside from the fact that “diazedine” is a lexical clipping of dimethylazetidine (diazedine).}}</ref><ref name="Morris2011b">{{cite web | last=Morris | first=Hamilton | title=Getting High on Krystle | website=VICE | date=28 September 2011 | url=https://www.vice.com/en/article/getting-high-on-krystle/ | access-date=13 October 2025 | quote=2 [LSZ] belongs to a small group of serotonergic psychedelics that are superior in potency to LSD. The first paper describing the pharmacology and composition of LSZ was written by a laboratory at Purdue University, where Leonard had been a student of the renowned chemist David Nichols. Although the research was published after Leonard's arrest, it is still likely that Leonard was aware of its contents. When I asked Dr. Nichols if he thought Pickard had actually produced LSZ, he said, "Leonard knew about our research, I'm sure of that." Rumors have circulated for years that LSZ was distributed on blotter paper (under the name λ), but there are no confirmed reports of its existence. The name diazedine is certainly ambiguous and could refer to pretty much anything, but I would bet a kilo of benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium that LSZ and diazedine are the same thing.}}</ref><ref name="Morris2011-S0E5">{{cite episode | credits = Hamilton Morris | date = 1 July 2011 | title = Getting High on Krystle: Underground LSD Palace | series = Hamilton's Pharmacopeia [web series] | number = S0E5 | publisher = Vice Media | url = https://vimeo.com/29699851 | transcript = [Web article] | transcript-url = https://www.vice.com/en/article/getting-high-on-krystle/}}</ref> Per Cole, "[diazedine] was also crazy, but nothing earth-shattering".<ref name="Morris2011a" /> Pickard and Skinner had high expectations for the drug and intended to produce and distribute it as an LSD alternative, but had difficulty scaling its synthesis due to high production costs and low yields.<ref name="Morris2011a" /><ref name="Cole2005">{{cite book | vauthors = Cole K | year = 2005 | title = Lysergic | publisher = Dog Ear Publishing | location = Indianapolis | isbn = 978-1598580075 | quote = [...] Diazadine [LSD analog] fails to be do-able big stress lines. [...]}}</ref> Pickard was a student of Nichols in his lab at Purdue University and was aware of the work on LSZ before it was published.<ref name="Morris2011b" /> Morris has speculated that "diazedine" (notably a contraction of "<u>di</u>methyl<u>aze</u>ti<u>dine</u>") is extremely likely to have been LSZ, although this remains unconfirmed.<ref name="Morris2011a" /><ref name="Morris2011b" /><ref name="Morris2011-S0E5" /> There have also been rumors for many years that LSZ was distributed for a time on blotter paper under the name "λ" ("lambda"), though this has likewise not been confirmed.<ref name="Morris2011b" />

LSZ was first definitely encountered as a novel designer drug, in Europe, in December 2013.<ref name="BrandtKavanaghWestphal2017" /><ref name="EMCDDA2014">European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). EMCDDA-Europol 2013 Annual Report on the implementation of Council Decision 2005/387/JHA. EMCDDA, Lisbon, 2014. http://www.emcdda.europa.eu/system/files/publications/814/TDAN14001ENN_475519.pdf "74. Lysergic acid 2,4-dimethylazetidide (‘LSZ’) ([(2S,4S)-2,4-dimethylazetidin-1-yl]-[(9R)- 7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-yl]methanone) — 10 December 2013, Slovenia."</ref><ref name="ACMD2014" /> It is known to have been produced and sold by the now-defunct psychedelic lysergamide manufacturer Lizard Labs in the 2010s and 2020s.<ref name="Niesporek2022">{{cite AV media | last=Niesporek | first=Tom | title=Der Hype um legales LSD in Deutschland: Wie das Verbot umgangen wird | trans-title=The hype surrounding legal LSD in Germany: How the ban is circumvented | time=2:10–8:12, 20:05–20:41 | language=German | publisher=VICE auf Deutsch | website=YouTube | date=17 August 2022 | url=https://www.youtube.com/watch?v=iVNCt2zyIaQ&t=130 | access-date=29 September 2025}}</ref><ref name="BrandtKavanaghWestphal2017" /><ref name="LizardLabs2024">{{cite web | title=The End of An Era: Lizard Labs to Permanently Close on 31st December 2024 | date=November 2024 | website=GetResponse | publisher=Lizard Labs | url=https://app.getresponse.com/view.html?x=a62b&m=BoLTp8&u=tQnqQ&z=Etdr9tg&o=pp_1 | access-date=29 September 2025 | archive-date=29 September 2025 | archive-url=https://archive.today/20250929030008/https://app.getresponse.com/view.html?x=a62b&m=BoLTp8&u=tQnqQ&z=Etdr9tg&o=pp_1 | url-status=bot: unknown }}</ref> The drug is said to have become a popular psychedelic drug and alternative to other lysergamides like LSD following its initial emergence.<ref name="BrandtKavanaghWestphal2020">{{cite journal | vauthors = Brandt SD, Kavanagh PV, Westphal F, Stratford A, Elliott SP, Dowling G, Halberstadt AL | title = Analytical profile of N-ethyl-N-cyclopropyl lysergamide (ECPLA), an isomer of lysergic acid 2,4-dimethylazetidide (LSZ) | journal = Drug Test Anal | volume = 12 | issue = 10 | pages = 1514–1521 | date = October 2020 | pmid = 32803833 | pmc = 9191644 | doi = 10.1002/dta.2911 | url = }}</ref><ref name="MallaroniMasonVinckenbosch2022" />

==Society and culture== ===Legal status=== ====Canada==== LSZ is not a controlled substance in Canada as of 2025.<ref name="CDSA">{{cite web | title=Controlled Drugs and Substances Act | website=Department of Justice Canada | url=https://laws-lois.justice.gc.ca/eng/acts/c-38.8/FullText.html | access-date=19 January 2026}}</ref>

====Europe==== LSZ is illegal in Switzerland as of December 2015,<ref name="DerBundesrat2015">{{cite web | url=https://www.admin.ch/opc/de/classified-compilation/20101220/index.html | title=Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien | publisher=Der Bundesrat | language=German}}</ref> in Denmark as of May 2015,<ref name="Lægemiddelstyrelsen2015">{{cite web | url=https://laegemiddelstyrelsen.dk/da/nyheder/2015/bekendtgoerelse-om-euforiserende-stoffer-ni-nye-stoffer-tilfoejet/ | title=Bekendtgørelse om euforiserende stoffer - ni nye stoffer tilføjet | publisher=Lægemiddelstyrelsen | language=Danish | date=31 August 2015}}</ref> and in Sweden as of January 2016.<ref name="Folkhälsomyndigheten2015">{{cite web | url=https://www.folkhalsomyndigheten.se/nyheter-och-press/nyhetsarkiv/2015/november/31-nya-amnen-kan-klassas-som-narkotika-eller-halsofarlig-vara/ | title=31 nya ämnen kan klassas som narkotika eller hälsofarlig vara | publisher=Folkhälsomyndigheten | language=Swedish | date=November 2015}}</ref> It is also illegal in France.<ref name="LegiFrance" />

====United Kingdom==== On June 10, 2014, the United Kingdom Advisory Council on the Misuse of Drugs (ACMD) recommended that LSZ be specifically named in the UK Misuse of Drugs Act as a class A drug despite not identifying any harm associated with its use.<ref name="ACMD2014">{{cite web | url=https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/318693/UpdateGenericDefinitionTryptamines.pdf | title=Update of the Generic Definition for Tryptamines | publisher=UK Home Office | date=10 June 2014 | access-date=10 June 2014 | author=ACMD|page=12}}</ref> The United Kingdom Home office accepted this advice and announced a ban of the substance to be enacted on 6 January 2015 as part of the Misuse of Drugs Act amended in 2014.<ref name="ACMD2014" />

====United States==== LSZ is not an explicitly controlled substance in the United States.<ref name="OrangeBook2026">{{citation | title = Orange Book: List of Controlled Substances and Regulated Chemicals (January 2026) | date = January 2026 | publisher = U.S. Department of Justice: Drug Enforcement Administration (DEA): Diversion Control Division | location = United States | url = https://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf}}</ref> However, it could be considered a controlled substance under the Federal Analogue Act if intended for human consumption.

==Research== LSZ has been patented as a potential anti-inflammatory drug by Charles D. Nichols and colleagues.<ref name="US20100016280A1">{{cite web | title=Low Dosage Serotonin 5-HT2A Receptor Agonist To Suppress Inflammation | website=Google Patents | date=10 July 2009 | url=https://patents.google.com/patent/US20100016280A1/en | access-date=13 October 2025}}</ref>

==See also== * Substituted lysergamide * Lizard Labs

==References== {{Reflist}}

==External links== * [https://isomerdesign.com/pihkal/explore/5363 LSZ - Isomer Design] * [https://psychonautwiki.org/wiki/LSZ LSZ - PsychonautWiki] * [https://erowid.org/chemicals/lsz/lsz.shtml LSZ - Erowid] * [https://www.bluelight.org/xf/threads/681365 The Big & Dandy LSZ Thread - Bluelight] * [https://tripsitter.com/lsz/ LSZ (Lysergic Acid Dimethylazetidide): Stronger Than LSD - TripSitter] * [https://tripsitter.com/psychedelics/lysergamides/#13_LSZ LSZ - Lysergamide Psychedelics - TripSitter] * [https://tripsit.me/factsheets/lsz LSZ - TripSit]

{{Psychedelics}} {{Serotonin receptor modulators}} {{Dopamine receptor modulators}} {{Ergolines}}

Category:5-HT1A agonists Category:5-HT2A agonists Category:5-HT2B agonists Category:5-HT2C agonists Category:Azetidines Category:Carboxamides Category:David E. Nichols Category:Designer drugs Category:Dopamine receptor modulators Category:Lizard Labs Category:Methyl compounds Category:Psychedelic lysergamides Category:Serotonin receptor modulators