Nor-LSD

Nor-LSD
Clinical data
Other namesnorLSD; 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
Drug classSerotonin receptor modulator; Serotonergic psychedelic; Hallucinogen
ATC code
  • None
Identifiers
  • (6aR,9R)-N,N-diethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide
CAS Number
PubChem CID
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.164.623 Edit this at Wikidata
Chemical and physical data
FormulaC19H23N3O
Molar mass309.413 g·mol−1
3D model (JSmol)
  • CCN(CC)C(=O)[C@H]1CN[C@@H]2CC3=CNC4=CC=CC(=C34)C2=C1
  • InChI=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
  • Key: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). It is the analogue of LSD in which the methyl group at the 6 position of the ergoline ring system has been removed.

Use and effects

According to Alexander Shulgin, nor-LSD showed no psychedelic effects at assessed doses of up to 500 μg in humans, whereas LSD was active at doses as low as 50 μg. Higher doses of nor-LSD do not appear to have been assessed.

Pharmacology

Pharmacodynamics

Nor-LSD showed 5- to 29-fold lower affinity for the serotonin 5-HT2 receptor compared to LSD (Ki = 30–158 nM vs. 5.4 nM, respectively). It also showed affinity for the serotonin 5-HT1 receptor. In another more recent study however, nor-LSD showed similar or even higher affinities, activational potencies, and/or efficacies at the serotonin 5-HT1A, 5-HT2A, and 5-HT2B receptors as LSD, whereas it showed 36-fold lower affinity for the serotonin 5-HT2C receptor compared to LSD.

Nor-LSD failed to completely substitute for LSD in rodent drug discrimination tests even at very high doses. The greatest degree of substitution with nor-LSD was 75% at a dose of 7,420 nM/kg, whereas 100% substitution occurred with LSD at a dose of 186 nM/kg (a 40-fold lower dose). The ED50Tooltip median effective dose was 2,594 nM/kg for nor-LSD and 46 nM/kg for LSD. 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. In another study, nor-LSD failed to produce LSD-like electroencephalogram (EEG) changes in rabbits.

Pharmacokinetics

Nor-LSD has been reported to occur as a metabolite of LSD in rats and humans.

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. There appears to be a length of about 3 carbon atoms that can be tolerated at the 6 position before potent psychedelic activity is lost.

History

Nor-LSD was first described in the scientific literature, by Yuji Nakahara and Tetsukichi Niwaguchi, by at least 1971.

See also

References

  1. 1 2 3 Nichols DE, Oberlender R, McKenna DJ (1991). "Stereochemical Aspects of Hallucinogenesis". In Watson RR (ed.). Biochemistry and Physiology of Substance Abuse. Vol. 3. Boca Raton, Fla.: CRC Press. pp. 1–39. ISBN 978-0-8493-4463-3. OCLC 26748320. TABLE 1 Effects of N-(6)-Alkyl Subtituents on LSD-Like Behavior and Serotonin Receptor Affinity in Rats [...]
  2. 1 2 3 4 5 6 7 8 Hoffman AJ (August 1987). Synthesis and pharmacological evaluation of N(6)-alkyl norlysergic acid N,N-diethylamide derivatives (Ph.D. thesis). Purdue University. Table 7. 5-HT2 binding affinity of N(6)-alkyl norLSD derivatives. [...]
  3. 1 2 3 4 5 6 Hoffman AJ, Nichols DE (September 1985). "Synthesis and LSD-like discriminative stimulus properties in a series of N(6)-alkyl norlysergic acid N,N-diethylamide derivatives". Journal of Medicinal Chemistry. 28 (9): 1252–1255. doi:10.1021/jm00147a022. PMID 4032428.
  4. 1 2 3 Pfaff RC, Huang X, Marona-Lewicka D, Oberlender R, Nichols DE (1994). "Lysergamides revisited". NIDA Research Monograph. 146: 52–73. PMID 8742794. TABLE 1. Drug discrimination ED50 values and receptor affinities of N(6)-alkyl-nor-LSD derivatives [...]
  5. 1 2 3 Jacob P, Shulgin AT (1994). "Structure-activity relationships of the classic hallucinogens and their analogs" (PDF). NIDA Research Monograph. 146: 74–91. PMID 8742795. Archived from the original (PDF) on August 5, 2023.
  6. 1 2 3 Shulgin AT (2003). "Basic Pharmacology and Effects". In Laing RR (ed.). Hallucinogens: A Forensic Drug Handbook. Forensic Drug Handbook Series. Elsevier Science. pp. 67–137. ISBN 978-0-12-433951-4.
  7. ↑ Luethi D, Hoener MC, Krähenbühl S, Liechti ME, Duthaler U (June 2019). "Cytochrome P450 enzymes contribute to the metabolism of LSD to nor-LSD and 2-oxo-3-hydroxy-LSD: Implications for clinical LSD use". Biochem Pharmacol. 164: 129–138. doi:10.1016/j.bcp.2019.04.013. PMID 30981875.
  8. ↑ Siddik ZH, Barnes RD, Dring LG, Smith RL, Williams RT (October 1979). "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". Biochemical Pharmacology. 28 (20): 3093–3101. doi:10.1016/0006-2952(79)90618-x. PMID 117811. 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.
  9. ↑ Nichols DE (October 2018). "Dark Classics in Chemical Neuroscience: Lysergic Acid Diethylamide (LSD)" (PDF). ACS Chemical Neuroscience. 9 (10): 2331–2343. doi:10.1021/acschemneuro.8b00043. PMID 29461039.
  10. ↑ Dolder P (2017). The Pharmacology of d-Lysergic Acid Diethylamide (LSD) (PDF) (Thesis). University of Basel. p. 112. doi:10.5451/UNIBAS-006786123. Retrieved 3 June 2025.
  11. ↑ Passie T, Halpern JH, Stichtenoth DO, Emrich HM, Hintzen A (2008). "The pharmacology of lysergic acid diethylamide: a review". CNS Neuroscience & Therapeutics. 14 (4): 295–314. doi:10.1111/j.1755-5949.2008.00059.x. PMC 6494066. PMID 19040555.
  12. ↑ Gumpper RH, Nichols DE (October 2024). "Chemistry/structural biology of psychedelic drugs and their receptor(s)". British Journal of Pharmacology bph.17361. doi:10.1111/bph.17361. PMID 39354889.
  13. ↑ Niwaguchi T, Nakahara Y (1971). "Studies on Lysergic Acid Diethylamide and Related Compounds. I. Synthesis of d-N6-Demethyl-lysergic Acid Diethylamide". Chemical and Pharmaceutical Bulletin. 19 (11): 2337–2341. doi:10.1248/cpb.19.2337. ISSN 0009-2363. Retrieved 3 June 2025.
  14. ↑ Niwaguchi T, Inoue T, Nakahara Y (March 1974). "Studies on enzymatic dealkylation of D-lysergic acid diethylamide (LSD)". Biochemical Pharmacology. 23 (6): 1073–1078. doi:10.1016/0006-2952(74)90007-0. PMID 4151050.