Iso-LSD

Iso-LSD, also known as d-iso-LSD, (+)-iso-LSD, or (5R-8S)-LSD, as well as N,N-diethylisolysergamide, is a serotonin receptor modulator of the lysergamide family related to lysergic acid diethylamide (LSD).^[2][3][4][5] It is the 8-position epimer of LSD, with iso-LSD being 8α (8S) and LSD being 8β (8R).^{[6][7][2][3][4][5]} Iso-LSD is also the N,N-diethyl derivative of isoergine (isolysergic acid amide; iso-LSA), a constituent found in morning glory seeds.^[2][8][9][5] Iso-LSD is one of four possible stereoisomers of LSD.^[10]

Iso-LSD

Clinical data
Other names	IsoLSD; I-LSD; d-Iso-LSD; (+)-Iso-LSD; (5R-8S)-LSD; Isolysergic acid diethylamide; N,N-Diethylisolysergamide; iso-Lysergic acid diethylamide; N,N-Diethyl-6-methyl-9,10-didehydroergoline-8α-carboxamide; d-Isolysergic acid diethylamide
Routes of administration	Oral
Drug class	Serotonin receptor modulator
ATC code	None
Pharmacokinetic data
Elimination half-life	12 hours[1]
Identifiers
IUPAC name (6aR,9S)-N,N-diethyl-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide
CAS Number	2126-78-5
PubChem CID	638252
IUPHAR/BPS	154
UNII	R1XBQ6NTFR
CompTox Dashboard (EPA)	DTXSID30858950
ECHA InfoCard	100.387.572
Chemical and physical data
Formula	C20H25N3O
Molar mass	323.440 g·mol−1
3D model (JSmol)	Interactive image
SMILES CCN(CC)C(=O)[C@@H]1CN([C@@H]2CC3=CNC4=CC=CC(=C34)C2=C1)C
InChI InChI=1S/C20H25N3O/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/h6-9,11,14,18,21H,4-5,10,12H2,1-3H3/t14-,18+/m0/s1 Key:VAYOSLLFUXYJDT-KBXCAEBGSA-N

Use and effects

According to Albert Hofmann and colleagues, iso-LSD is inactive as a psychedelic in humans at doses of up to 500 μg, which is up to 25 times the minimum given doses of LSD (i.e., 20–50 μg).^{[11][12][13][2][14][15]} In other sources, iso-LSD was also stated as being inactive at doses of up to 50 μg/kg (3.5 mg for a 70-kg person), whereas LSD is active at a dose of 1 μg/kg (70 μg for a 70-kg person).^[16][17] Hence, iso-LSD is inactive in humans at doses of up to 50 times those of a common psychedelic dose of LSD and at doses of up to 175 times the minimum dose of LSD.^[16][17][17] Alexander Shulgin has additionally reported that iso-LSD was inactive at a dose of 4 mg orally.^[18] The related drug isoergine is known to be active in terms of psychoactive and hallucinogenic effects at doses of 2 to 5 mg orally.^{[11][19][16][20][21][22][23][24]}

Pharmacology

Pharmacodynamics

Iso-LSD shows significant affinity for serotonin receptors.^[2][8][9] It had an affinity (IC₅₀Tooltip half-maximal inhibitory concentration) of about 200 nM for serotonin receptors in rat brain membranes.^[2][8][9] For comparison, LSD had an affinity of about 8 to 10 nM in the studies, while isoergine had an affinity of 100 to 200 nM and ergine (LSA) had an affinity of about 200 nM.^[8][9][25] Hence, iso-LSD showed about 10- to 30-fold lower affinity for serotonin receptors than LSD but had similar affinity for the receptors as ergine and isoergine.^{[2][8][9][25]} Despite these findings however, iso-LSD showed only 0.12% of the antiserotonergic activity of LSD (~1,000-fold lower in comparison) in the isolated rat uterus.^{[26][22][27][28][17][29]}

In studies by David E. Nichols and colleagues, iso-LSD fully substituted for LSD in rodent drug discrimination tests.^[30] Full substitution occurred at a dose of 0.32 mg/kg and its ED₅₀Tooltip median effective dose was 0.14 mg/kg, whereas the LSD training dose was 0.08 mg/kg.^[30] Iso-LSD was about 7-fold less potent than LSD in terms of ED₅₀ in this assay.^[30] In other studies, the drug had about 3.7% of the toxic potency of LSD in rabbits (presumably in terms of LD₅₀Tooltip median lethal dose) and, unlike LSD, was not pyretogenic.^[27][22]

Pharmacokinetics

Iso-LSD is said to have identical metabolism to LSD.^[31] It has a longer elimination half-life than LSD.^[1] Their half-lives were 12 hours and 4.2 hours, respectively.^[1]

Chemistry

Chemical structures of LSD and its three stereoisomers, including iso-LSD ((+)-iso-LSD).

The LSD molecule has two chiral centers at carbons 5 and 8 of the ergoline ring system and hence there are four possible enantiomeric stereoisomers of LSD.^[10][7] Iso-LSD, also known as d-iso-LSD, (+)-iso-LSD, or (5R-8S)-LSD, is one of four possible stereoisomers.^[10][7] The other isomers are LSD (d-LSD, (+)-LSD, or (5R,8R)-LSD), l-iso-LSD ((–)-iso-LSD or (5S,8R)-iso-LSD), and l-LSD ((–)-LSD or (5S,8S)-LSD).^[10][7] None of them are known to have significant psychoactivity in humans besides LSD.^[10][7][15]

LSD is easily epimerized into iso-LSD with base.^[5][32][33] Consequently, iso-LSD is a common synthetic contaminant in chemical synthesis of LSD.^[5] Iso-LSD can be easily epimerized back into LSD.^[33] LSD can degrade into iso-LSD depending on temperature, solvent and pH, among other factors.^[34][18] In clinical studies, up to 30% of LSD administered in capsules has been found to isomerize into iso-LSD.^[34]

Iso-LSD is said to be a metabolite of LSD in animals and humans.^[35][31][36] However, according to other sources, iso-LSD not a metabolite of LSD but is instead only a contaminant.^[1][37]

History

Iso-LSD was first described in the scientific literature, by Albert Hofmann and colleagues, in the 1940s.^[35][13][12] The psychedelic effects of LSD were discovered by Hofmann in 1943 when he was using column chromatography to separate LSD from iso-LSD that had resulted as an impurity during the synthesis of LSD.^[35]