2,3-Dihydro-LSD

vanc 6 2,3-DH-LSD 2D.svg skin-invert-image 165px 2,3-DH-LSD 3D.png bg-transparent 225px Oral Serotonergic psychedelic; Hallucinogen None None 53947245 67024742 2,3-DH-LSD; DH-LSD; 2,3-Dihydrolysergic acid diethylamide; N,N-Diethyl-6-methyl-9,10-didehydro-2,3-dihydroergoline-8β-carboxamide (6aR,9R)-N,N-diethyl-7-methyl-5,5a,6,6a,8,9-hexahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide 20 27 3 1 CCN(CC)C(=O)[C@H]1CN([C@@H]2CC3CNC4=CC=CC(=C34)C2=C1)C 1S/C20H27N3O/c1-4-23(5-2)20(24)14-9-16-15-7-6-8-17-19(15)13(11-21-17)10-18(16)22(3)12-14/h6-9,13-14,18,21H,4-5,10-12H2,1-3H3/t13?,14-,18-/m1/s1 JBWYWLQLZXGQJF-JDPNFYKBSA-N 2,3-Dihydro-LSD, or 2,3-DH-LSD, also known as 2,3-dihydrolysergic acid diethylamide, is a psychedelic drug of the lysergamide family related to lysergic acid diethylamide (LSD). Nichols DE Potential Psychotomimetics: Bromomethoxyamphetamines and Structural Congeners of Lysergic Acid 26 May 1973 University of Iowa 1194694085 https://bitnest.netfirms.com/external/Theses/Nichols1973#page=35 Analogs of lysergic acid have been prepared which include certain features of the LSD molecule but do not contain an indole nucleus. The most impressive finding in this regard is that of Gorodetzky and Isbell (69) who found that in human volunteers, 2,3-dihydro-LSD 22 possesses approximately one-sixth and one-eighth the potency of LSD in producing mydriasis and mental effects, respectively. It should be noted that the time of onset and peak activity was somewhat delayed from that of LSD, and the possibility of an in vivo aromatization process, or the generation of an active metabolite cannot be ruled out. Brimblecombe RW, Pinder RM Indolealkylamines and Related Compounds Hallucinogenic Agents Bristol 98–144 1975 Wright-Scientechnica 978-0-85608-011-1 2176880 OL4850660M https://bitnest.netfirms.com/external/Books/978-0-85608-011-1 One other compound of interest is d-2,3-dihydrolysergic acid diethylamide, which is from one-sixth to one-eighth as potent as LSD but with a slower onset and a longer duration of action; it is not known whether this reflects in vivo dehydrogenation to LSD (Gorodetzky and Isbell, 1964). [...] Table 4.3.—COMPARATIVE HALLUCINOGENIC POTENCIES IN MAN OF DERIVATIVES OF D-LYSERGIC ACID* [...] Nichols DE, Oberlender R, McKenna DJ Stereochemical Aspects of Hallucinogenesis Watson RR Biochemistry and Physiology of Substance Abuse 3 CRC Press Boca Raton, Fla. 1991 978-0-8493-4463-3 26748320 1–39 https://archive.org/details/biochemistryphys0003unse/ https://bitnest.netfirms.com/external/Books/BiochemistryPhysiologySubstanceAbuse3.1 9. 2,3-Dihydro-LSD This analogue was synthesized as the 3β-H isomer.150 It was active in man but had only 15% the potency of LSD,160 with a slower onset and longer duration. The activity of this derivative may be a consequence of in vivo rearomatization to LSD itself.123,166 Gorodetzky CW, Isbell H A comparison of 2,3-dihydro-lysergic acid diethylamide with LSD-25 Psychopharmacologia 6 3 229–233 September 1964 5319153 10.1007/BF00404013 https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=2a1c8e0d8ae022723549bdf59d15ce2655334211 2025-03-02 2025-06-03 https://web.archive.org/web/20250302180655/https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=2a1c8e0d8ae022723549bdf59d15ce2655334211 dead It is the analogue of LSD in which the 2,3- double bond in the indole ring within the ergoline ring system has been hydrogenated. Shulgin AT Hoffmeister F, Stille G Chemistry of Psychotomimetics Psychotropic Agents, Part III: Alcohol and Psychotomimetics, Psychotropic Effects of Central Acting Drugs Berlin 55 Part 3 3–29 1982 10.1007/978-3-642-67770-0_1 Handbook of Experimental Pharmacology Springer Berlin Heidelberg 978-3-642-67772-4 8130916 https://books.google.com/books?id=mrT8CAAAQBAJ https://bitnest.netfirms.com/external/10.1007/978-3-642-67770-0_1 Hydrogenation of the indolic double bond (to give 2,3-dihydro-LSD) reduces the potency by an order of magnitude (GORODETZKY and ISBELL, 1964). Use and effects The drug produces similar autonomic and psychoactive effects as LSD in humans, although its hallucinogenic effects are less pronounced. It has been found to possess about one-sixth to one-eighth (i.e., ~15% overall) of the potency of LSD in inducing mydriasis (pupil dilation) and psychedelic effects, respectively, in humans. Nichols DE Chemistry and Structure-Activity Relationships of Psychedelics Current Topics in Behavioral Neurosciences 36 1–43 2018 28401524 10.1007/7854_2017_475 978-3-662-55878-2 Reducing the 2,3-bond of the indole nucleus results in a compound with about one-eighth the activity of LSD (Gorodetzky and Isbell 1964). It was reported to have a delayed onset of action relative to LSD, and it was speculated that “a metabolic change to a more active substance” might be the explanation. It might be noted that 2,3-dihydroindoles can be fairly readily oxidized to indoles, so such an oxidative transformation might take place in the body, perhaps by action of a mixed function oxidase in the liver. Nunes F LSD--an historical reevaluation Journal of Chemical Education 45 11 688–691 November 1968 5696280 10.1021/ed045p688 1968JChEd..45..688N Table 1. A Comparison of Psychic Effectiveness with Serotonin Antagonism [...] Fanchamps A Some Compounds With Hallucinogenic Activity Ergot Alkaloids and Related Compounds 567–614 1978 10.1007/978-3-642-66775-6_8 Springer Berlin Heidelberg Berlin, Heidelberg 978-3-642-66777-0 http://link.springer.com/10.1007/978-3-642-66775-6_8 3 June 2025 2.3-Dihydrolysergic acid diethylamide (see general formula in the chapter .. Chemical Background," Fig. 15) induces LSD-like autonomic and mental changes; its potency is estimated by GORODETZKY and ISBELL (1964) at about 15% of that of LSD. Its activity in inducing hyperthermia in rabbits is only 4% of the LSD activity (Sandoz Res. Lab., 1959). [...] Table 2. Psychotomimetic activity and some pharmacodynamic effects of structural analogues of LSD Mangner TJ Potential Psychotomimetic Antagonists. N,N -diethyl-1-methyl-3-aryl-1,2,5,6-tetrahydropyridine-5-carboxamides. 1978 10.7302/11268 Ph.D. University of Michigan https://www.proquest.com/openview/f845a6810749d00f70305960adfde737/ 1 June 2025 https://web.archive.org/web/20250601032023/https://www.proquest.com/openview/f845a6810749d00f70305960adfde737/ Table 1. Human psychotomimetic potencies of LSD analogs. [...] Two other variations at the 2-position of LSD include an isolated metabolite of LSD, 2-oxy-LSD (37), which did not produce any psychological effects after oral administration of 300 μg,63 and the 2,3-dihydro-LSD (38) which was found to be one-sixth to one-eighth as potent as LSD with a slower onset of action.64 More specifically, 2,3-dihydro-LSD is psychedelic at doses of 3.0 to 4.5μg/kg (210–315μg for a 70-kg person), while LSD is hallucinogenic at doses of 0.5 to 1.0μg/kg (35–70μg for a 70-kg person). In addition to its greatly reduced potency compared to LSD, 2,3-dihydro-LSD has a delayed onset and time to peak effects relative to LSD. The duration of 2,3-dihydro-LSD was roughly 8 to 12hours and was longer than that of LSD (which had a duration of about 7hours in the study) as well. Interactions Psychedelic drug#Interactions Trip killer#Serotonergic psychedelic antidotes Pharmacology Pharmacodynamics In rabbits, 2,3-dihydro-LSD had about 4% (1/25th) of the potency of LSD in inducing hyperthermia, while in mice, it was "equally toxic" (presumably referring to LD50 median lethal dose) as LSD. Sankar DV LSD - A Total Study Westbury, N.Y. 69, 102 1975 72-95447 978-0-9600290-3-7 PJD Publications https://www.samorini.it/doc1/alt_aut/sz/sankar-lsd-a-total-study.pdf#page=68 Another derivative of LSD-25, the 2,3-dihydro-lysergic acid diethylamide (where the double bond in the indole ring is saturated by hydrogenation) has been shown to be approximately 4% as potent as LSD in producting increased temperature in rabbits. Isbell (9), studied the properties of 2,3-dihydro-lysergic acid diethylamide and contrasted them to those of LSD-25. He found that the effects of 2,3-dihydro-LSD-25 are much less pronounced and appear more slowly than that of LSD-25, being about one-fifth of LSD-25. This would also show that the intact indole ring is important in the manifestation of the properties of LSD. [...] 2,3-Dihydro-LSD is 1/5 to 1/8 as potent as LSD25 in man (9). Pharmacokinetics It is possible that 2,3-dihydro-LSD may function as a prodrug and aromatize/dehydrogenate into LSD or metabolize into another active metabolite in vivo. Relatedly, 2,3-dihydroindoles can be fairly readily aromatized into indoles, and 2,3-dihydro-LSD has been detected as a metabolite of radiolabeled LSD in the isolated perfused rat liver in vitro, supporting the possibility of interconversion between the two compounds. Siddik ZH, Barnes RD, Dring LG, Smith RL, Williams RT The metabolism of lysergic acid DI[14C]ethylamide ([14C]LSD) in the isolated perfused rat liver Biochemical Pharmacology 28 20 3081–3091 October 1979 518707 10.1016/0006-2952(79)90617-8 Alternatively, 2,3-dihydro-LSD might be absorbed more slowly or penetrate the blood–brain barrier more gradually than LSD. History 2,3-Dihydro-LSD was first described in the scientific literature by Charles Gorodetzky and Harris Isbell at the Addiction Research Center of the National Institute of Mental Health (subsequently part of the National Institute on Drug Abuse) by 1964. However, it had first been synthesized and studied in animals by Botand Berde and Rudolph Bircher at Sandoz Pharmaceuticals, but their findings were unpublished. Sandoz Pharmaceuticals supplied the 2,3-dihydro-LSD used by Gorodetzky and Isbell in their clinical study. See also Substituted lysergamide 9,10-Dihydro-LSD 2-Oxo-LSD 2-Oxo-3-hydroxy-LSD References External links 2,3-Dihydro-LSD - Isomer Design Category:Diethylamides Category:Enantiopure drugs Category:LSD Category:Psychedelic lysergamides