LSZ, as the (S,S)- isomer LA-SS-Az, has been reported to have a dose range of 100 to 200μg or 100 to 300μgorally, with a typical dose estimate of 150 or 200μg.[1][2][6] This dose range is notably higher than that ofLSD, which is 50 to 200μg with a typical dose of about 100μg.[21][22][23][24][1] According toDavid E. Nichols however, LSZ is approximatelyequipotent with LSD based on humananecdotal reports.[5] Theduration of LSZ is reported to be in the range of 3 to 11hours, with a median duration of around 8hours.[2] This was shorter than the duration of the LSDprodrug1P-LSD, which had a duration range of 6 to 14hours and a median duration of about 10hours in the same study.[2] 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.[1][2][4]
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified.Refs:[25][26][27][7][8][28][29][30][4]
LSZ produces thehead-twitch response, a behavioral proxy ofpsychedelic-like effects, in rodents.[31][1][6] It shows about the samepotency as LSD andAL-LAD in producing this effect.[31][1] However, LSZ shows a weaker maximal head-twitch response than LSD or AL-LAD.[6] This might be due to lower efficacy at the serotonin 5-HT2A receptor or stronger actions at other receptors like the serotonin 5-HT1A or 5-HT2C receptor.[6] LSZ also substitutes for LSD in rodentdrug discrimination tests.[1][7] It was about 1.8-fold more potent than LSD in this assay.[1][7] All three isomers of LSZ fully substituted for LSD in rodentdrug discrimination tests, but the (S,S)- isomer was the most potent and was the only isomer that was more potent than LSD.[6][7] In addition, only the (S,S) isomer fully substituted for the LSD-likeselective serotonin 5-HT1A receptorfull agonist andpartial ergolineLY-293284.[6][7] In contrast to LSZ, LSD itself does not substitute for LY-293284 in drug discrimination tests.[7]
Nichols and colleagues likeRobert Oberlender had initially attempted to do this research by employing the closely related and very similar compoundLA-Aziridine in the 1980s, but this drug proved to be highlychemically unstable such thatin-vivo studies were precluded.[7][9][10][11] With the development of LSZ, the team determined that the (S,S)- isomer, LA-SS-Az, was the mostpotent and hence most optimal configuration of LSZ in terms of serotonin 5-HT2A receptor activation and psychedelic-like effects in animals.[6][7] In addition, the conformation of LSD within thecrystal structure of the closely related serotonin5-HT2B receptor was later found to be essentially superimposable with the structure of LA-SS-Az.[4][35][29] Similar findings were made withvirtual docking studies with the serotonin 5-HT2A receptor.[4][35] LSZ, as LA-SS-Az, is among the only known analogues of LSD modified at theamide to have similar or greater psychedelic-type potency.[4][7]
According to Krystle Cole in an interview with journalist and researcherHamilton Morris, the LSDclandestine manufacturersWilliam Leonard Pickard andGordon Todd Skinner hadsynthesized and experimented with a psychedelic drug they called "diazedine" around the year 2000.[12][13][14] Per Cole, "[diazedine] was also crazy, but nothing earth-shattering".[12] 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 lowyields.[12][36] Pickard was a student of Nichols in his lab at Purdue University and was aware of the work on LSZ before it was published.[13] Morris has speculated that "diazedine" (notably a contraction of "dimethylazetidine") is extremely likely to have been LSZ, although this remains unconfirmed.[12][13][14] There have also been rumors for many years that LSZ was distributed for a time onblotter paper under the name "λ" ("lambda"), though this has likewise not been confirmed.[13]
LSZ was first definitely encountered as a noveldesigner drug, inEurope, in December 2013.[6][15][20] It is known to have been produced and sold by the now-defunct psychedelic lysergamide manufacturerLizard Labs in the 2010s and 2020s.[37][6][38] The drug is said to have become a popular psychedelic drug and alternative to other lysergamides like LSD following its initial emergence.[16][2]
On June 10, 2014, theUnited KingdomAdvisory Council on the Misuse of Drugs (ACMD) recommended that LSZ be specifically named in theUK Misuse of Drugs Act as a class A drug despite not identifying any harm associated with its use.[20] 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 theMisuse of Drugs Act amended in 2014.[20]
^abcdefghijNichols DE (2018).Chemistry and Structure-Activity Relationships of Psychedelics. Curr Top Behav Neurosci. Vol. 36. pp. 1–43.doi:10.1007/7854_2017_475.ISBN978-3-662-55878-2.PMID28401524.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.{{cite book}}:|journal= ignored (help)
^abcNichols 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.PMID29461039.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
^abcdefghijklmnopqrstuvwxyzaaabacNichols DE, Frescas S, Marona-Lewicka D, Kurrasch-Orbaugh DM (September 2002). "Lysergamides of isomeric 2,4-dimethylazetidines map the binding orientation of the diethylamide moiety in the potent hallucinogenic agent N,N-diethyllysergamide (LSD)".J Med Chem.45 (19):4344–4349.doi:10.1021/jm020153s.PMID12213075.
^abcdeMorris H (1 May 2011)."Life Is a Cosmic Giggle on the Breath of the Universe". Vice Magazine. Retrieved2011-06-15.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).
^abcdeMorris, Hamilton (28 September 2011)."Getting High on Krystle".VICE. Retrieved13 October 2025.2 [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.
^abEuropean 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."
^abHalberstadt AL, Geyer MA (2018). "Effect of Hallucinogens on Unconditioned Behavior".Behavioral Neurobiology of Psychedelic Drugs. Curr Top Behav Neurosci. Vol. 36. pp. 159–199.doi:10.1007/7854_2016_466.ISBN978-3-662-55878-2.PMC5787039.PMID28224459.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).
^Yu B, Becnel J, Zerfaoui M, Rohatgi R, Boulares AH, Nichols CD (November 2008). "Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency".J Pharmacol Exp Ther.327 (2):316–323.doi:10.1124/jpet.108.143461.PMID18708586.
^Wagmann L, Richter LH, Kehl T, Wack F, Bergstrand MP, Brandt SD, Stratford A, Maurer HH, Meyer MR (July 2019). "In vitro metabolic fate of nine LSD-based new psychoactive substances and their analytical detectability in different urinary screening procedures".Anal Bioanal Chem.411 (19):4751–4763.doi:10.1007/s00216-018-1558-9.PMID30617391.
^abcDuan W, Cao D, Wang S, Cheng J (January 2024). "Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants".Chem Rev.124 (1):124–163.doi:10.1021/acs.chemrev.3c00375.PMID38033123.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
^abcGumpper RH, Nichols DE (October 2024). "Chemistry/structural biology of psychedelic drugs and their receptor(s)".Br J Pharmacol bph.17361.doi:10.1111/bph.17361.PMID39354889.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'. [...]
^Cole K (2005).Lysergic. Indianapolis: Dog Ear Publishing.ISBN978-1598580075.[...] Diazadine [LSD analog] fails to be do-able big stress lines. [...]
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