12-Methoxy-LSD

Pharmaceutical compound From Wikipedia, the free encyclopedia

12-Methoxy-LSD is a drug of the ergoline and lysergamide families and a derivative of lysergic acid diethylamide (LSD).^[1]^[2]^[3]^[4] In terms of chemical structure, 12-methoxy-LSD is to LSD as 5-MeO-DMT is to dimethyltryptamine (DMT), with 12-methoxy-LSD notably containing 5-MeO-DMT within its conformationally constrained structure.^[5] Both 12-methoxy-LSD and its analogue 12-hydroxy-LSD have been described as non-hallucinogenic in humans.^[1]^[2]^[3]^[6] However, in other more recent reports, 12-hydroxy-LSD produced psychedelic-like effects in rodents^[7] and was said to have similar activity as LSD in humans.^[8]

Other names12-MeO-LSD; "5-MeO-LSD"; "5-Methoxy-LSD"; 9,10-Didehydro-N,N-diethyl-6-methyl-12-methoxyergoline-8β-carboxamide

Drug classSerotonin receptor modulator

CAS Number

50484-99-6

PubChem CID

3039341

Quick facts Clinical data, Other names ...

12-Methoxy-LSD
Clinical data


Other names	12-MeO-LSD; "5-MeO-LSD"; "5-Methoxy-LSD"; 9,10-Didehydro-N,N-diethyl-6-methyl-12-methoxyergoline-8β-carboxamide
Drug class	Serotonin receptor modulator
Identifiers
IUPAC name (6aR,9R)-N,N-diethyl-1-methoxy-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide
CAS Number	50484-99-6
PubChem CID	3039341
ChemSpider	2302827
CompTox Dashboard (EPA)	DTXSID30198505
Chemical and physical data
Formula	C₂₁H₂₇N₃O₂
Molar mass	353.466 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES CCN(CC)C(=O)[C@H]1CN([C@@H]2CC3=CNC4=C3C(=C(C=C4)OC)C2=C1)C
InChI InChI=1S/C21H27N3O2/c1-5-24(6-2)21(25)14-9-15-17(23(3)12-14)10-13-11-22-16-7-8-18(26-4)20(15)19(13)16/h7-9,11,14,17,22H,5-6,10,12H2,1-4H3/t14-,17-/m1/s1 Key:AYFDTTGGASATFS-RHSMWYFYSA-N

Interactions

Pharmacology

It has been reported that 12-methoxy-LSD does not produce hallucinogenic effects in humans.^[1]^[2]^[3]^[6] However, it is nonetheless pharmacologically active in animal studies.^[1] The drug's effects in rabbits include antiserotonergic activity (20% of that of LSD) and hyperthermia (dose ratio relative to LD₅₀Tooltip median lethal dose of 1:17 for 12-methoxy-LSD and 1:725 for LSD).^[1] In addition, like LSD, it is highly potent in terms of lethality, with a median lethal dose (LD₅₀) of 0.1 mg/kg i.v.Tooltip intravenous administration in rabbits (relative to 0.1 mg/kg for LSD).^[1]^[3]^[4] 12-Methoxy-LSD also produces LSD-like electroencephalogram (EEG) changes in rabbits.^[9]

Presumably 12-methoxy-LSD acts as an agonist of serotonin and dopamine receptors, as with LSD and other related lysergamides, but its pharmacology has not been studied with modern techniques.^[1]^[3]

Chemistry

Synthesis

The chemical synthesis of 12-substituted lysergamides is described as being very difficult.^[7]

Analogues

An analogue of 12-methoxy-LSD is 12-hydroxy-LSD, which would be structurally akin to bufotenin (5-HO-DMT).^[1]^[3]^[8] As with 12-methoxy-LSD, it has been reported that 12-hydroxy-LSD is inactive as a psychedelic in humans.^[1] Contrary to this report however, Michael Valentine Smith claimed in his 1981 book Psychedelic Chemistry that 12-hydroxy-LSD has "about the same activity as LSD".^[8] In addition, 12-hydroxy-LSD has been found to substitute for LSD in rodent drug discrimination tests with about 20% of its potency.^[7]

History

12-Methoxy-LSD was first described in the scientific literature by 1967.^[1] Subsequently, it was further described in the 1970s and 1980s.^[3]^[4]^[6]^[9]^[8]^[2]

References

[1]
M. Taeschler (1967). "Pharmacology of Psychotomimetic Agents". In Brill H, Cole JO, Deniker P, Hippius H, Bradley PB (eds.). Neuro-psycho-pharmacology: Proceedings of the Fifth International Congress of the Collegium Internationale Neuropsychopharmacologicum. Washington, D.C., 28-31 March 1966. International Congress Series. Vol. 129. Amsterdam: Excerpta Medica. pp. 393–397. ISSN 0531-5131. OCLC 458719. Fig. 2. Listed are several pharmacodynamic properties of various lysergic acid derivatives: Ps = psychotomimetic activity in man; P.I. = pyretogenic index (ratio of the i.v. LD50 and the dose producing an increase in rectal temperature of 1°C in rabbits); Tox. = i.v. LD50 in rabbits; 5-HT = antiserotonin activity in isolated rat uterus expressed in percentages of that for LSD-25. It is evident that the psychotomimetic action does not correlate with 5-HT antagonism nor with the toxicity of the compound. A close correlation is observed with the pyretogenic index (i.e. the specific pyretogenic action in rabbits. [...] LSD: 5-HT: 100. TOX.: 0,3. P.I.: 725. Ps.: +. [...] 12 CH3O-: 5-HT: 20. TOX.: 0,1. P.I.: 17. Ps.: –.
[2]
Donald A. Cooper (1989). "Future Synthetic Drugs of Abuse". Proceedings of the International Symposium on the Forensic Aspects of Controlled Substances: March 28-April 1, 1988, Forensic Science Research and Training Center, FBI Academy, Quantico, Virginia. Laboratory Division, Federal Bureau of Investigation, U.S. Department of Justice. pp. 79–103 (81). ISBN 978-0-932115-09-6. Retrieved 18 March 2025. The assessment of a particular LSD derivative as a candidate for a future [Controlled Substance Analog (CsA)] involves the consideration of several points. The most important are those attempts made by other researchers to modify the structure of LSD while retaining hallucinogenic activity. To date, all attempts to modify the tetracyclic ring system have resulted in a loss of hallucinogenic activity. For instance, of the four possible C-8 stereoisomers only the dextro isomer of LSD is hallucinogenic (Rothlin 1957a). Modification of the amide alkyl substituents also reduces hallucinogenic activity substantially (Usdin and Efron 1972). Additionally, substitution with either a hydroxyl or a methoxy at the C-12 of LSD results in a compound with no hallucinogenic activity (Usdin and Efron 1972), whereas a comparably substituted methoxyindolealkylamine appears to always be hallucinogenic (Gessner and Page 1962). The only structural modification which results in the maintenance of hallucinogenic activity on par with LSD is the substitution of either a methyl or an acetyl to the indole nitrogen (Rothlin 1957b).
[3]
Usdin E, Efron DH (1972). Psychotropic Drugs and Related Compounds. National Institute of Mental Health. pp. 96, 100. ASIN B002X3CDIY. 277. 12-METHOXY LYSERGIC ACID DIETHYLAMIDE. 9,10-Didehydro-N,N-diethyl-6-methyl-12-methoxy-ergoline-8β-carboxamide. [...] LD50: 0.1 mg./kg./i.v/R. (1460). Action: Not [hallucinogen (H)] (1460). [...] 1460. Taeschler, M. In: 'Neuropsychopharmacology.' Ed. by Brill, H., Cole, J.O., Deniker, P., Hippius, H., & Bradley, P.B. Amsterdam: Excerpta Medica Foundation (1967), pp. 393-397.
[4]
D. V. Siva Sankar (1975). "Molecular Investigations: Relations Between Molecular Structure and Psychobiological Activity / Molecular Aspects: Structure-Activity Relations" (PDF). LSD - A Total Study. Westbury, N.Y.: PJD Publications. pp. 65–106 (77, 82, 95). ISBN 978-0-9600290-3-7. LCCN 72-95447. STRUCTURAL DETAILS OF SOME LYSERGATES [...] 12-Methoxy-LSD [...] TABLE I [...] COMPOUND: 12-Methoxy lysergic acid diethylamide. Chemical Name: 12-Didehydro-N,N-diethyl-6- methoxy-ergoline-8β-carboxamide. LD50: 0.1 mg/kg/iv/R. [...] Abbreviations used: m for mouse, r for rat and R for rabbit. [...] TABLE II Structure and Biological Activities of Lysergates [...] Compound No.: 11. R1: C2H5. R2: C2H5. R3: H. R4: H. R5: OCH3. R6: H. R7: CH3. Hallucinogenic Activity: ?. Pyretogenic Effect: ?. Anti-HT: ?. Excitation Syndrome: ?. Toxicity: ?.
[5]
"Ergoline-8-beta-carboxamide, 9,10-didehydro-N,N-diethyl-12-methoxy-6-methyl-". PubChem. Retrieved 18 March 2025.
[6]
Mangner TJ (1978). Potential Psychotomimetic Antagonists. N,n -diethyl-1-methyl-3-aryl-1, 2, 5, 6-tetrahydropyridine-5-carboxamides (Ph.D. thesis). University of Michigan. doi:10.7302/11268. Archived from the original on 30 March 2025. Table 1. Human psychotomimetic potencies of LSD analogs. [...] Compound: 28 [(12-hydroxy-LSD)]. R1: C2H5. R2: C2H5. R3: H. R4: H. R5: OH. Rel Act (Ref): – (60). [...] Compound: 29 [(12-methoxy-LSD)]. R1: C2H5. R2: C2H5. R3: H. R4: H. R5: OCH3. Rel Act (Ref): – (60). [...] –, inactive. [...] The final two entries in Table 1, 12-hydroxy-LSD (28) and 12-methoxy-LSD (29), were reported to be inactive by Taeschler,60 although no details were given.
[7]
Pfaff RC, Huang X, Marona-Lewicka D, Oberlender R, Nichols DE (1994). "Lysergamides revisited". NIDA Research Monograph. 146: 52–73. PMID 8742794. Ring substitution at the C(12) or C(13) positions is fairly difficult. Because entire doctoral theses have been written about the total synthesis of lysergic acid, it is apparent that the synthesis of derivatives modified at the 12-, 13-, or 14-position would be quite a formidable task. Nevertheless, the 12-hydroxy compound was prepared years ago. The authors obtained a sample of this and performed drug discrimination (DD) studies in LSD-trained rats. It had unremarkable properties, with only about 20 percent of the potency of LSD (Pffaf et al., unpublished observations).
[8]
Smith M (1981). "[Chapter 7:] LSD". Psychedelic Chemistry. Loompanics Unlimited. pp. 103–137 (136). ISBN 978-0-915179-10-7. Retrieved 18 March 2025. 2,3-dihydro-LSD can be converted directly to 12-hydroxy-LSD, which has about the same activity as LSD and this process is also given below.
[9]
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. 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.