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13-Hydroxy-LSD

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13-Hydroxy-LSD
Clinical data
Other names13-Hydroxylysergic acid diethylamide; 13-OH-LSD; N,N-Diethyl-13-hydroxy-6-methyl-9,10-didehydroergoline-8β-carboxamide
ATC code
  • None
Identifiers
  • (6aR,9R)-N,N-diethyl-2-hydroxy-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide
PubChem CID
Chemical and physical data
FormulaC20H25N3O2
Molar mass339.439 g·mol−1
3D model (JSmol)
  • CCN(CC)C(=O)[C@H]1CN([C@@H]2CC3=CNC4=CC(=CC(=C34)C2=C1)O)C
  • InChI=1S/C20H25N3O2/c1-4-23(5-2)20(25)13-6-15-16-8-14(24)9-17-19(16)12(10-21-17)7-18(15)22(3)11-13/h6,8-10,13,18,21,24H,4-5,7,11H2,1-3H3/t13-,18-/m1/s1
  • Key:DZJOIBRTROBFRQ-FZKQIMNGSA-N

13-Hydroxy-LSD is a lysergamide and a metabolite of the psychedelic drug lysergic acid diethylamide (LSD).[1][2][3][4] It is a major metabolite of LSD in rats and guinea pigs but a minor metabolite of LSD in monkeys and humans.[1][4] Following its formation, 13-hydroxy-LSD undergoes further metabolism via glucuronidation.[1][2][3][4] Little is known about the specific enzymes responsible for generation of LSD metabolites such as 13-hydroxy-LSD in humans.[3][5]

According to David E. Nichols in 2016, the pharmacology of hydroxylated metabolites of LSD like 13-hydroxy-LSD has not been studied.[6] Nichols has posited that metabolism of LSD into active metabolites with potent dopamine receptor activity may be responsible for the delayed-onset dopaminergic stimulus effects of LSD in rodent drug discrimination tests.[6][7][8] Relatedly, lergotrile's corresponding metabolite 13-hydroxylergotrile is several-fold more potent as a dopamine receptor agonist than lergotrile itself in vitro.[6][9] However, more research is needed to assess the activity of 13-hydroxy-LSD and its potential involvement in LSD's effects.[6] In any case, metabolites of LSD, possibly including 13-hydroxy-LSD, have been reported to be pharmacologically active with LSD-like effects in animals, although details do not appear to have been provided.[10][4]

The 13 position of the ergoline ring system as in LSD and 13-hydroxy-LSD corresponds to the 6 position of the indole ring as in simple tryptamines.[11] 6-Hydroxy-DMT has been found to be active but less potent than dimethyltryptamine (DMT) in animals and to be inactive in humans at the assessed doses.[12][13][14][15][16] Similarly, it showed very low affinity for the serotonin 5-HT2 receptors.[17]

13-Hydroxy-LSD was first described in the scientific literature by at least 1963.[18][11]

See also

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References

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  1. ^ a b c 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. In animals, metabolism of LSD is highly species dependent, but generally seems to follow several pathways. Aromatic hydroxylation leads to 13- and 14-hydroxy LSD, which are primarily excreted as glucuronides.57 Metabolites are secreted in the bile and excreted via the gut, with negligible amounts of unchanged drug found in feces or urine. [...] The major metabolites in rats and guinea pigs (urine and bile) were glucuronic acid conjugates of 13- and 14-hydroxy-LSD. guinea pigs excreted significant amounts of 2-oxo-LSD in urine and bile. Lysergic acid ethylamide (LAE) was a minor urinary metabolite in both species. In rat livers perfused with [14C]-LSD, Siddik et al.59 identified the glucuronides of 13- and 14-hydroxyLSD, as well as 2-oxo-LSD, LAE, and nor-LSD. LSD had a unique metabolic profile in rhesus monkeys. Their urine contained at least nine metabolites. Four of them were identified as 13- and 14-hydroxy-LSD (as glucuronic acid conjugates), LAE, and a naphthostyril derivative. Glucuronic acid conjugates of 13- and 14-hydroxy-LSD were present in only small amounts in rhesus monkeys, setting them apart from rats and guinea pigs. [...] Canezin et al.63 found the following LSD metabolites in human urine: nor-LSD, LAE, 2-oxo-LSD, 2-oxy-3-hydroxy-LSD, 13- and 14-hydroxy-LSD as glucuronides, lysergic acid ethyl-2- hydroxyethylamide (LEO), and "trioxylated LSD." [...] In order to characterize and quantify better the human metabolites of LSD, Dolder et al.64 recently developed and validated a liquid chromatography triple quadrupole tandem mass spectrometry (LC-MS/MS) method for the quantification of LSD, iso-LSD, 2-oxo-3-OH-LSD, and nor-LSD in plasma samples from 24 healthy subjects after administration of 100 μg (free base) LSD in a clinical trial. In addition, recently described in vitro metabolites, including LAE, lysergic acid LEO, 2-oxo-LSD, trioxylatedLSD, and 13- and 14-hydroxy-LSD, could be identified. [...] LSD was quantified in the plasma samples of the 24 subjects of the clinical trial. Iso-LSD, 2-oxo-3-OH-LSD, nor-LSD, LAE, LEO, 13/14-hydroxy-LSD, and 2-oxo-LSD could be detected only sporadically, and concentrations were too low for quantification.
  2. ^ a b Libânio Osório Marta RF (August 2019). "Metabolism of lysergic acid diethylamide (LSD): an update". Drug Metab Rev. 51 (3): 378–387. doi:10.1080/03602532.2019.1638931. PMID 31266388. Furthermore, it seems to occur an aromatic hydroxylation of LSD at positions 13 and 14 to form 13-hydroxyLSD and 14-hydroxy-LSD, respectively (Lim et al. 1988). The urinary excretion of 13- and 14-hydroxy-LSD glucuronides from LSD users point to a probable presence of 13- and 14-hydroxy-LSD (Canezin et al. 2001). However, before Steuer et al. (2017) investigation, the chemical structure of 13- or 14-hydroxy LSD metabolites in humans was not completely defined. [...] Recently, iso-LSD, O-H-LSD, Nor-LSD, LAE, LEO, 2-oxo-LSD, 13 and 14-hydroxy-LSD were positively detected in human plasma samples after a controlled clinical trial, but were too low for quantification (Dolder et al. 2018). [...] The data obtained by Inoue et al. (1980a) suggest that LSD biotransformation is performed by at least three enzyme systems, in which cytochrome P450 plays an important role. Briefly, the diethylamide group at the 8-position, the N-methyl group at the 6-position and the aromatic proton at the 13-position undergo changes, respectively (Inoue et al. 1980a, 1980b).
  3. ^ a b c Meyer MR, Maurer HH (February 2011). "Absorption, distribution, metabolism and excretion pharmacogenomics of drugs of abuse". Pharmacogenomics. 12 (2): 215–233. doi:10.2217/pgs.10.171. PMID 21332315. It is rapidly metabolized to the following five metabolites which have been identified in urine or blood from human users: N-demethyl-LSD (nor-LSD), 2-oxoLSD, 2-oxo-3-hydroxy-LSD, 13-hydroxyLSD and 14-hydroxy-LSD [187–189]. The 13- and 14-hydroxy metabolites are additionally excreted as glucuronides [188]. [...] 2-oxo-3-hydroxy-LSD was shown to be the main human urinary metabolite with concentrations four- to 40-times higher than that of LSD [187,188,191]. As concluded by Yu in his review on indolalkylamines, almost nothing is known regarding the contribution of specific drug-metabolizing enzymes to the production of individual LSD metabolites in humans.
  4. ^ a b c d 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". Biochem Pharmacol. 28 (20): 3093–3101. doi:10.1016/0006-2952(79)90618-x. PMID 117811. 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.
  5. ^ Meyer, Markus R.; Maurer, Hans H. (18 April 2012). "Drugs of Abuse (Including Designer Drugs)". Metabolism of Drugs and Other Xenobiotics. Wiley. p. 429–463. doi:10.1002/9783527630905.ch16. ISBN 978-3-527-32903-8. Retrieved 7 June 2025. LSD is a semisynthetic derivative of ergot alkaloids from the fungus Claviceps purpurea. LSD is supposed to act as a 5-HT2 receptor agonist producing sensory alteration and euphoria [122]. It is metabolized to the following five metabolites: N-demethyl-LSD (nor-LSD), 2-oxo-LSD, 2-oxo-3-hydroxy-LSD, 13-hydroxy-LSD, and 14-hydroxy-LSD [72–74]. The 13- and 14-hydroxy metabolites are additionally excreted as glucuronides [74]. 2-Oxo-3-hydroxy-LSD was shown to be the main human urinary metabolite with concentrations 4–40 times higher than that of LSD [73–75]. In incubations of LSD with human liver microsomes and hepatocytes, 2,3-dihydroxy-LSD could be identified [71]. So far, the contribution and importance of specific enzymes in the formation of the LSD main metabolites such as 2-oxo-3-hydroxy-LSD still remains unclear.
  6. ^ a b c d Nichols DE (April 2016). Barker EL (ed.). "Psychedelics". Pharmacological Reviews. 68 (2): 264–355. doi:10.1124/pr.115.011478. ISSN 0031-6997. PMC 4813425. PMID 26841800.
  7. ^ Marona-Lewicka D, Nichols DE (October 2007). "Further evidence that the delayed temporal dopaminergic effects of LSD are mediated by a mechanism different than the first temporal phase of action". Pharmacol Biochem Behav. 87 (4): 453–461. doi:10.1016/j.pbb.2007.06.001. PMID 17618679.
  8. ^ Marona-Lewicka D, Chemel BR, Nichols DE (April 2009). "Dopamine D4 receptor involvement in the discriminative stimulus effects in rats of LSD, but not the phenethylamine hallucinogen DOI". Psychopharmacology (Berl). 203 (2): 265–277. doi:10.1007/s00213-008-1238-0. PMID 18604600.
  9. ^ Parli CJ, Schmidt B, Shaar CJ (May 1978). "Metabolism of lergotrile to 13-hydroxy lergotrile, a potent inhibitor of prolactin release in vitro". Biochem Pharmacol. 27 (9): 1405–1408. doi:10.1016/0006-2952(78)90131-4. PMID 29651.
  10. ^ Dolder P (2017). The Pharmacology of d-Lysergic Acid Diethylamide (LSD) (PDF) (Thesis). University of Basel. p. 112. doi:10.5451/UNIBAS-006786123. Out of the various LSD metabolites, 13-hydroxy-LSD and LAE were found to be active in animals (43).
  11. ^ a b Szara S (September 1963). "Enzymatic formation of a phenolic metabolite from lysergic acid diethylamide by rat liver microsomes". Life Sci (1962). 9: 662–670. doi:10.1016/0024-3205(63)90151-6. PMID 14068038. [...] it is highly probable that the hydroxy group of the new metabolite is in the 13-position of the lysergic acid ring, which corresponds to the 6-position of the indole structure. [...] It is hoped that the available techniques can eventually be adapted for studying the excretion of (13-) hydroxy-LSD in the urine of human subjects after taking LSD. [...] It has been suggested earlier7 that hydrogenation of indoles might produce biologically active metabolites. It is an intriguing possibility that the already highly active LSD might be transformed into an even more active metabolite. That this is a possibility is indicated by reported data5 that even the glucuronide (the supposedly detoxified product) of the probable (13-) hydroxy-LSD showed blocking action against serotonin in isolated uterus. Efforts are being made to enzymatically prepare and isolate enough metabolite to test its biological, behavioral and psychotropic activity. [...] Lysergic acid diethylamide - although metabolized by both rat and guinea pig liver tissues - is hydroxylated by rat (and not by guinea pig) liver microsomes, probably in the 13-position of the lysergic acid nucleus. [...] 5. M. B. Slaytor and S. E. Wright, J. Med. Pharm. Chem. 5, 483 (1962).
  12. ^ Shulgin, Alexander; Shulgin, Ann (September 1997). TiHKAL: The Continuation. Berkeley, California: Transform Press. ISBN 0-9630096-9-9. OCLC 38503252. "6-HO-DMT is a minor metabolite of DMT in man, and it was studied for the same reasons. Could this compound play a role in explaining the activity of the parent dialkylamine? It was explored in a series of subjects who had responded spectacularly to DMT. The five volunteers in this study were former opium addicts who were serving sentences for violation of United States narcotics laws. They were administered 6-HO-DMT at either 0.75 mg/kg (one subject) or 1.0 mg/kg (four subjects) and reported no differences from the inactive placebo control. The objective measures (blood pressure, respiration and heart rate, pupillary dilation) confirmed this absence of activity at this level. The active control drug was DMT itself, and it showed the expected responses in all regards." [...] "It is pretty generally accepted that 6-HO-DMT is inactive. I am not too surprised. There are so few things with open and exposed hydroxyl groups that succeed in making it through the lipid barriers that protect to the brain."
  13. ^ Shulgin AT (1976). "Psychotomimetic Agents". In Gordon M (ed.). Psychopharmacological Agents: Use, Misuse and Abuse. Medicinal Chemistry: A Series of Monographs. Vol. 4. Academic Press. pp. 59–146. doi:10.1016/b978-0-12-290559-9.50011-9. ISBN 978-0-12-290559-9. In fact, animal studies with 6-hydroxy-N,N-dimethyltryptamine suggested that the compound was indeed more potent that its parent (Szara and Hearst, 1962). [...] 6-Hydroxy-5-methoxy-N,Ndiniethyltryptamine [(XXXV), R1 = OCH3 , R 2 = R3 = CH3] appeared to be less potent than 5-methoxy-N,N-dimethyltryptamine (Taborsky et al., 1966) and 6-hydroxy-5-methoxytryptamine [(XXXV), R1 = OCH3 , R2 = R3 = H] was less potent than 5-methoxytryptamine (Taborsky et al., 1965). In animal studies (Uyeno, 1969) as well as human studies (Rosenberg et al., 1963), 6-hydroxy-N,N-dimethyltryptamine [(XXXV), R 1 = H, R2 = R3 = CH3] was inactive at 1 mgfkg, whereas N,N-dimethyltryptamine is clinically effective at this dosage. [...] The present evidence indicates that chemical substitution on the 6 position of the tryptamine system destroys the psychotomimetic potential of the compound.
  14. ^ Glennon RA, Rosecrans JA (1982). "Indolealkylamine and phenalkylamine hallucinogens: a brief overview". Neurosci Biobehav Rev. 6 (4): 489–497. doi:10.1016/0149-7634(82)90030-6. PMID 6757811. 6-Hydroxy DMT (3f) displays only weak behavioral activity in animals [10, 73, 74] and is not hallucinogenic in man [55]. It may be argued that the lipid solubility of 6-hydroxy DMT, like that of bufotenine, will not allow it to penetrate into the brain; this might account for its inactivity. [...] It might be speculated that 6-hydroxy DMT, like bufotenine, would display more activity if it were made more lipid soluble by, for example, acylation of the hydroxyl group. Although this is an intriguing possibility, its likelihood is not supported by the low order of activity of its O-methyl ether 6-OMe DMT (3g) [20,27].
  15. ^ Uyeno ET (1971). "Relative potency of amphetamine derivatives and N,N-dimethyltryptamines". Psychopharmacologia. 19 (4): 381–387. doi:10.1007/BF00404382. PMID 5565249.
  16. ^ Rosenberg DE, Isbell H, Miner EJ (February 1963). "Comparison of a placebo, N-dimethyltryptamine, and 6-hydroxy-N-dimethyltryptamine in man". Psychopharmacologia. 4: 39–42. doi:10.1007/BF00429362. PMID 14050410.
  17. ^ Sard H, Kumaran G, Morency C, Roth BL, Toth BA, He P, Shuster L (October 2005). "SAR of psilocybin analogs: discovery of a selective 5-HT 2C agonist". Bioorg Med Chem Lett. 15 (20): 4555–4559. doi:10.1016/j.bmcl.2005.06.104. PMID 16061378.
  18. ^ Caldwell J, Sever PS (October 1974). "The biochemical pharmacology of abused drugs. I. Amphetamines, cocaine, and LSD". Clin Pharmacol Ther. 16 (4): 625–638. doi:10.1002/cpt1974164625. PMID 4607666. Szara71 also found that rat and guinea pig liver microsomes metabolized LSD, but suggested that in rat (but not guinea pig) the product was 13-hydroxy-LSD. Studies in this laboratory using both 3H-LSD and 14C-LSD have shown six metabolites of LSD in rat bile, two of which appear to be conjugates of hydroxylated metabolites.* [...] *Siddik, Z. H.: Unpublished data. [...] 71. Szara, S.: Enzymatic formation of a phenolic metabolite from lysergic acid diethylamide by rat liver microsomes, Life Sci. 1:662-670, 1963.
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