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| Other names | 2,3-DH-LSD; DH-LSD; 2,3-Dihydrolysergic acid diethylamide;N,N-Diethyl-6-methyl-9,10-didehydro-2,3-dihydroergoline-8β-carboxamide |
| Routes of administration | Oral[1] |
| Drug class | Serotonergic psychedelic;Hallucinogen |
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| Chemical and physical data | |
| Formula | C20H27N3O |
| Molar mass | 325.456 g·mol−1 |
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2,3-Dihydro-LSD, or2,3-DH-LSD, also known as2,3-dihydrolysergic acid diethylamide, is apsychedelic drug of thelysergamide family related tolysergic acid diethylamide (LSD).[2][3][4][1] It is theanalogue of LSD in which the 2,3-double bond in theindolering within theergolinering system has beenhydrogenated.[5][6][4]
The drug produces similarautonomic andpsychoactive effects as LSD in humans, although itshallucinogenic effects are less pronounced.[6][1] It has been found to possess about one-sixth to one-eighth (i.e., ~15% overall) of thepotency of LSD in inducingmydriasis (pupil dilation) andpsychedelic effects, respectively, in humans.[7][2][4][3][5][8][9][10][1] More specifically, 2,3-dihydro-LSD is psychedelic at doses of 3.0 to 4.5 μg/kg (210–315 μg for a 70-kg person), while LSD is hallucinogenic at doses of 0.5 to 1.0 μg/kg (35–70 μg for a 70-kg person).[8][1]
In addition to its greatly reduced potency compared to LSD, 2,3-dihydro-LSD has a delayedonset and time to peak effects relative to LSD.[7][4][2][3][10][1] Theduration of 2,3-dihydro-LSD was roughly 8 to 12 hours and was longer than that of LSD (which had a duration of about 7 hours in the study) as well.[1]
In rabbits, 2,3-dihydro-LSD had about 4% (1/25th) of the potency of LSD in inducinghyperthermia, while in mice, it was "equallytoxic" (presumably referring toLD50Tooltip median lethal dose) as LSD.[9][6][1]
It is possible that 2,3-dihydro-LSD may function as aprodrug andaromatize/dehydrogenate into LSD ormetabolize into anotheractive metabolitein vivo.[7][4][2][3][1] Relatedly, 2,3-dihydroindoles can be fairly readily aromatized intoindoles,[7] and 2,3-dihydro-LSD has been detected as a metabolite ofradiolabeled LSD in the isolated perfused ratliverin vitro, supporting the possibility of interconversion between the two compounds.[11] Alternatively, 2,3-dihydro-LSD might beabsorbed more slowly or penetrate theblood–brain barrier more gradually than LSD.[1]
2,3-Dihydro-LSD was first described in thescientific literature by Charles Gorodetzky andHarris Isbell at theAddiction Research Center of theNational Institute of Mental Health (subsequently part of theNational Institute on Drug Abuse) by 1964.[1] However, it had first beensynthesized and studied in animals by Botand Berde and Rudolph Bircher atSandoz Pharmaceuticals, but their findings were unpublished.[1] Sandoz Pharmaceuticals supplied the 2,3-dihydro-LSD used by Gorodetzky and Isbell in their clinical study.[1]
{{cite journal}}: CS1 maint: bot: original URL status unknown (link)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.
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* [...]
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
Hydrogenation of the indolic double bond (to give 2,3-dihydro-LSD) reduces the potency by an order of magnitude (GORODETZKY and ISBELL, 1964).
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).
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.
Table 1. A Comparison of Psychic Effectiveness with Serotonin Antagonism [...]
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
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