{{cs1 config|name-list-style=vanc|display-authors=6}} {{About|6-nor-LSD|other nor-LSD compounds|Nor-LSD (disambiguation)}} {{Infobox drug | drug_name = | image = Nor-LSD.svg | image_class = skin-invert-image | width = 175px | image2 = Nor-LSD 3D.png | image_class2 = bg-transparent | width2 = 225px
<!-- Clinical data --> | pronounce = | tradename = | Drugs.com = | MedlinePlus = | licence_CA = | licence_EU = | DailyMedID = | licence_US = | pregnancy_AU = | pregnancy_category = | dependency_liability = | addiction_liability = | routes_of_administration = | class = Serotonin receptor modulator; Serotonergic psychedelic; Hallucinogen | ATC_prefix = None | ATC_suffix =
<!-- Legal status --> | legal_status =
<!-- Pharmacokinetic data --> | bioavailability = | protein_bound = | metabolism = | metabolites = | onset = | elimination_half-life = | duration_of_action = | excretion =
<!-- Identifiers --> | CAS_number = 35779-43-2 | CAS_supplemental = | PubChem = 169713 | PubChemSubstance = | IUPHAR_ligand = | DrugBank = | ChemSpiderID = 148419 | UNII = | KEGG = | ChEBI = | ChEMBL = 21343 | NIAID_ChemDB = | PDB_ligand = | synonyms = norLSD; ''N'',''N''-Diethyl-6-norlysergamide; ''N''-Desmethyllysergic acid diethylamide; ''N''-Desmethyl-LSD; Norlysergic acid diethylamide; ''N''-Demethyl-LSD; 9,10-Didehydro-''N'',''N''-diethylergoline-8β-carboxamide; H-LAD; NORLAD; NOR-LAD; 6-Nor-LSD
<!-- Chemical data --> | IUPAC_name = (6''aR'',9''R'')-''N'',''N''-diethyl-4,6,6''a'',7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide | C=19 | H=23 | N=3 | O=1 | SMILES = CCN(CC)C(=O)[C@H]1CN[C@@H]2CC3=CNC4=CC=CC(=C34)C2=C1 | StdInChI = 1S/C19H23N3O/c1-3-22(4-2)19(23)13-8-15-14-6-5-7-16-18(14)12(10-20-16)9-17(15)21-11-13/h5-8,10,13,17,20-21H,3-4,9,11H2,1-2H3/t13-,17-/m1/s1 | StdInChIKey = SUXLVXOMPKZBOV-CXAGYDPISA-N }}
'''Nor-LSD''', or '''norLSD''', also known as '''''N'',''N''-diethyl-6-norlysergamide''' or as '''''N''-desmethyllysergic acid diethylamide''' ('''''N''-desmethyl-LSD'''), is a serotonin receptor modulator and putative psychedelic of the lysergamide family related to lysergic acid diethylamide (LSD).<ref name="NicholsOberlenderMcKenna1991">{{cite book | vauthors=Nichols DE, Oberlender R, McKenna DJ | chapter=Stereochemical Aspects of Hallucinogenesis | veditors=Watson RR | title=Biochemistry and Physiology of Substance Abuse | volume=3 | publisher=CRC Press | publication-place=Boca Raton, Fla. | year=1991 | isbn=978-0-8493-4463-3 | oclc=26748320 | pages=1–39 | url=https://archive.org/details/biochemistryphys0003unse/ | chapter-url=https://bitnest.netfirms.com/external/Books/BiochemistryPhysiologySubstanceAbuse3.1 | quote=TABLE 1 Effects of N-(6)-Alkyl Subtituents on LSD-Like Behavior and Serotonin Receptor Affinity in Rats [...]}}</ref><ref name="Hoffman_1987" /><ref name="Hoffman_1985">{{cite journal | vauthors = Hoffman AJ, Nichols DE | title = Synthesis and LSD-like discriminative stimulus properties in a series of N(6)-alkyl norlysergic acid N,N-diethylamide derivatives | journal = Journal of Medicinal Chemistry | volume = 28 | issue = 9 | pages = 1252–1255 | date = September 1985 | pmid = 4032428 | doi = 10.1021/jm00147a022 }}</ref><ref name="Pfaff_1994">{{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://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=dbc3139042e2b2baf5a2e6c65edc6afe9b131f79 | quote = TABLE 1. Drug discrimination ED50 values and receptor affinities of N(6)-alkyl-nor-LSD derivatives [...] }}</ref> It is the analogue of LSD in which the methyl group at the 6 position of the ergoline ring system has been removed.<ref name="Hoffman_1987" /><ref name="Hoffman_1985" />
==Use and effects== According to Alexander Shulgin, nor-LSD showed no psychedelic effects at assessed doses of up to 500{{nbsp}}μg in humans, whereas LSD was active at doses as low as 50{{nbsp}}μg.<ref name="Jacob_1994">{{cite journal | vauthors = Jacob P, Shulgin AT | title = Structure-activity relationships of the classic hallucinogens and their analogs | journal = NIDA Research Monograph | volume = 146 | pages = 74–91 | date = 1994 | pmid = 8742795 | 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="Shulgin_2003">{{cite book | vauthors = Shulgin AT | veditors = Laing RR | chapter = Basic Pharmacology and Effects | title = Hallucinogens: A Forensic Drug Handbook | pages = 67–137 | year = 2003 | publisher = Elsevier Science | series = Forensic Drug Handbook Series | 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 }}</ref> Higher doses of nor-LSD do not appear to have been assessed.<ref name="Jacob_1994" /><ref name="Shulgin_2003" />
==Pharmacology== ===Pharmacodynamics=== Nor-LSD showed 5- to 29-fold lower affinity for the serotonin 5-HT<sub>2</sub> receptor compared to LSD (K<sub>i</sub> = 30–158{{nbsp}}nM vs. 5.4{{nbsp}}nM, respectively).<ref name="NicholsOberlenderMcKenna1991" /><ref name="Hoffman_1987">{{cite thesis | vauthors = Hoffman AJ | degree = Ph.D. | title = Synthesis and pharmacological evaluation of N(6)-alkyl norlysergic acid N,N-diethylamide derivatives | date = August 1987 | publisher = Purdue University | url = https://bitnest.netfirms.com/external/Theses/Hoffman1987 | quote = Table 7. 5-HT2 binding affinity of N(6)-alkyl norLSD derivatives. [...] }}</ref><ref name="Pfaff_1994" /> It also showed affinity for the serotonin 5-HT<sub>1</sub> receptor.<ref name="Hoffman_1987" /> In another more recent study however, nor-LSD showed similar or even higher affinities, activational potencies, and/or efficacies at the serotonin 5-HT<sub>1A</sub>, 5-HT<sub>2A</sub>, and 5-HT<sub>2B</sub> receptors as LSD, whereas it showed 36-fold lower affinity for the serotonin 5-HT<sub>2C</sub> receptor compared to LSD.<ref name="LuethiHoenerKrähenbühl2019">{{cite journal | vauthors = Luethi D, Hoener MC, Krähenbühl S, Liechti ME, Duthaler U | title = Cytochrome P450 enzymes contribute to the metabolism of LSD to nor-LSD and 2-oxo-3-hydroxy-LSD: Implications for clinical LSD use | journal = Biochem Pharmacol | volume = 164 | issue = | pages = 129–138 | date = June 2019 | pmid = 30981875 | doi = 10.1016/j.bcp.2019.04.013 | url = }}</ref>
Nor-LSD failed to completely substitute for LSD in rodent drug discrimination tests even at very high doses.<ref name="NicholsOberlenderMcKenna1991" /><ref name="Hoffman_1987" /><ref name="Hoffman_1985" /> The greatest degree of substitution with nor-LSD was 75% at a dose of 7,420{{nbsp}}nM/kg, whereas 100% substitution occurred with LSD at a dose of 186{{nbsp}}nM/kg (a 40-fold lower dose).<ref name="Hoffman_1987" /><ref name="Hoffman_1985" /> The {{Abbrlink|ED<sub>50</sub>|median effective dose}} was 2,594{{nbsp}}nM/kg for nor-LSD and 46{{nbsp}}nM/kg for LSD.<ref name="Hoffman_1987" /><ref name="Hoffman_1985" /> Hence, nor-LSD was approximately 56-fold less potent than LSD in terms of producing LSD-like effects in rodents and failed to produce full LSD-like effects even at the highest assessed dose.<ref name="Hoffman_1987" /><ref name="Hoffman_1985" /> In another study, nor-LSD failed to produce LSD-like electroencephalogram (EEG) changes in rabbits.<ref name="SiddikBarnesDring1979">{{cite journal | vauthors = Siddik ZH, Barnes RD, Dring LG, Smith RL, Williams RT | title = The fate of lysergic acid DI[14C]ethylamide ([14C]LSD) in the rat, guinea pig and rhesus monkey and of [14C]iso-LSD in rat | journal = Biochemical Pharmacology | volume = 28 | issue = 20 | pages = 3093–3101 | date = October 1979 | pmid = 117811 | doi = 10.1016/0006-2952(79)90618-x | quote = EEG studies. Synthetic and biosynthetic metabolites of LSD were injected intravenously into conscious restrained male chinchilla rabbits. With LSD itself, de-ethyl-LSD, 12-hydroxy-LSD, 12-methoxy-LSD, 13-hydroxy-LSD, 13-methoxy-LSD and 13-hydroxy-LSD glucuronide, a persistent alerting EEG trace was seen as indicated by an increase in frequency and decrease in amplitude of the waveform. No changes were observed after administration of lysergic acid, di-LSD-disulphide [10], nor-LSD, 14-hydroxy-LSD-glucuronide, 14-methoxy-LSD, lumi-LSD or the metabolic 2-oxo-LSD. [...] Preliminary studies have indicated that some of the metabolites of LSD, as well as the drug itself. produce an activation of the EEG of the conscious rabbit suggesting they may have central activity. These findings will be published elsewhere.}}</ref>
===Pharmacokinetics=== Nor-LSD has been reported to occur as a metabolite of LSD in rats and humans.<ref name="Nichols_2018">{{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 | doi = 10.1021/acschemneuro.8b00043 | url = https://shaunlacob.com/wp-content/uploads/2020/12/DC-LSD.pdf }}</ref><ref name="Dolder_2017">{{cite thesis | vauthors = Dolder P | title = The Pharmacology of d-Lysergic Acid Diethylamide (LSD) | pages = 112 | date = 2017 | doi = 10.5451/UNIBAS-006786123 | publisher = University of Basel | url = https://core.ac.uk/download/pdf/154350706.pdf#page=112 | access-date = 3 June 2025 }}</ref><ref name="Passie_2008">{{cite journal | vauthors = Passie T, Halpern JH, Stichtenoth DO, Emrich HM, Hintzen A | title = The pharmacology of lysergic acid diethylamide: a review | journal = CNS Neuroscience & Therapeutics | volume = 14 | issue = 4 | pages = 295–314 | date = 2008 | pmid = 19040555 | pmc = 6494066 | doi = 10.1111/j.1755-5949.2008.00059.x }}</ref>
==Chemistry== ===Derivatives=== Derivatives of nor-LSD substituted at the 6 position include LSD (METH-LAD; 6-methyl), ETH-LAD (6-ethyl), PRO-LAD (6-propyl), BU-LAD (6-butyl), AL-LAD (6-allyl), and PARGY-LAD (6-propynyl), among others.<ref name="Pfaff_1994" /><ref name="Jacob_1994" /><ref name="Shulgin_2003" /> There appears to be a length of about 3{{nbsp}}carbon atoms that can be tolerated at the 6 position before potent psychedelic activity is lost.<ref name="Gumpper_2024">{{cite journal | vauthors = Gumpper RH, Nichols DE | title = Chemistry/structural biology of psychedelic drugs and their receptor(s) | journal = British Journal of Pharmacology | date = October 2024 | article-number = bph.17361 | pmid = 39354889 | doi = 10.1111/bph.17361 }}</ref>
==History== Nor-LSD was first described in the scientific literature, by Yuji Nakahara and Tetsukichi Niwaguchi, by at least 1971.<ref name="Niwaguchi_1971">{{cite journal | vauthors = Niwaguchi T, Nakahara Y | title = Studies on Lysergic Acid Diethylamide and Related Compounds. I. Synthesis of d-N6-Demethyl-lysergic Acid Diethylamide | journal = Chemical and Pharmaceutical Bulletin | volume = 19 | issue = 11 | pages = 2337–2341 | date = 1971 | doi = 10.1248/cpb.19.2337 | issn = 0009-2363 | doi-access = free | url = https://www.jstage.jst.go.jp/article/cpb1958/19/11/19_11_2337/_pdf | access-date = 3 June 2025 }}</ref><ref name="Niwaguchi_1974">{{cite journal | vauthors = Niwaguchi T, Inoue T, Nakahara Y | title = Studies on enzymatic dealkylation of D-lysergic acid diethylamide (LSD) | journal = Biochemical Pharmacology | volume = 23 | issue = 6 | pages = 1073–1078 | date = March 1974 | pmid = 4151050 | doi = 10.1016/0006-2952(74)90007-0 }}</ref>
==See also== * Substituted lysergamide
==References== {{Reflist}}
==External links== * [https://isomerdesign.com/pihkal/explore/5346 Nor-LSD - Isomer Design]
{{Psychedelics}} {{Serotonin receptor modulators}} {{Ergolines}}
Category:5-HT2A agonists Category:5-HT2B agonists Category:Diethylamino compounds Category:Enantiopure drugs Category:LSD Category:Psychedelic drug metabolites Category:Psychedelic lysergamides Category:Serotonin receptor modulators