Analytical profile, in vitro metabolism and behavioral properties of the lysergamide 1P‐AL‐LAD
Simon D. Brandt, Pierce V. Kavanagh, Folker Westphal, Benedikt Pulver, Hannes M Schwelm, Kyla Whitelock, Alexander Stratford, Volker Auwärter, Adam L. Halberstadt
Drug Testing and Analysis May 7, 2022 DOI: 10.1002/dta.3281 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Dose | 491 nmol/kg (ED50 for 1P-AL-LAD); 174.9 nmol/kg (ED50 for AL-LAD) |
| Measures | head twitch response (HTR) |
| Topics | LSD Psilocybin |
| Keywords | Metabolite Hallucinogen Pharmacology In vivo Metabolism In vitro Microsome Hydroxylation Ed50 Prodrug Stereochemistry |
| Citations | 14 |
| Key findings | 1P-AL-LAD acts as a prodrug that converts to AL-LAD and induces a dose-dependent head twitch response in mice with an ED50 of 491 nmol/kg, nearly three times less potent than AL-LAD. |
Abstract
Abstract Lysergic acid diethylamide (LSD) is known to induce powerful psychoactive effects in humans, which cemented its status as an important tool for clinical research. A range of analogues and derivatives has been investigated over the years, including those classified as new psychoactive substances. This study presents the characterization of the novel lysergamide N , N ‐diethyl‐1‐propanoyl‐6‐(prop‐2‐en‐1‐yl)‐9,10‐didehydroergoline‐8β‐carboxamide (1P‐AL‐LAD) using various mass spectrometric, gas‐ and liquid chromatographic and spectroscopic methods. In vitro metabolism studies using pooled human liver microsomes (pHLM) confirmed that 1P‐AL‐LAD converted to AL‐LAD as the most abundant metabolite consistent with the hypothesis that 1P‐AL‐LAD may act as a prodrug. Fourteen metabolites were detected in total; metabolic reactions included hydroxylation of the core lysergamide ring structure or the N 6 ‐allyl group, formation of dihydrodiol metabolites, N ‐dealkylation, N 1 ‐deacylation, dehydrogenation, and combinations thereof. The in vivo behavioral activity of 1P‐AL‐LAD was evaluated using the mouse head twitch response (HTR), a 5‐HT 2A ‐mediated head movement that serves as a behavioral proxy in rodents for human hallucinogenic effects. 1P‐AL‐LAD induced a dose‐dependent increase in HTR counts with an inverted U‐shaped dose–response function, similar to lysergic acid diethylamide (LSD), psilocybin, and other psychedelics. Following intraperitoneal injection, the median effective dose (ED 50 ) for 1P‐AL‐LAD was 491 nmol/kg, making it almost three times less potent than AL‐LAD (174.9 nmol/kg). Previous studies have shown that N 1 ‐substitution disrupts the ability of lysergamides to activate the 5‐HT 2A receptor; based on the in vitro metabolism data, 1P‐AL‐LAD may induce the HTR because it acts as a prodrug and is metabolized to AL‐LAD after administration to mice.
Comparable studies
Other preclinical and animal studies on LSD, most cited first.
Citations in the library
Cited by 8
- Stimulant and hallucinogenic novel psychoactive substances; an update Expert Review of Clinical Pharmacology November 2, 2023
- Identification of LSD analogs, 1cP-AL-LAD, 1cP-MIPLA, 1V-LSD and LSZ in sheet products. Forensic Toxicology July 1, 2023
- Synthesis and analytical characterization of 1-(2-thienoyl)-6-allyl-nor-d-lysergic acid diethylamide (1T-AL-LAD). Drug Testing and Analysis April 1, 2025
- The use of prodrugs as drugs of abuse Wiley Interdisciplinary Reviews Forensic Science March 19, 2024
- Analytical and behavioral characterization of N-ethyl-N-isopropyllysergamide (EIPLA), an isomer of N6 -ethylnorlysergic acid N,N-diethylamide (ETH-LAD). Drug Testing and Analysis February 1, 2024
and 3 more in the library
Cites 25
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- Phenomenology, Structure, and Dynamic of Psychedelic States Current Topics in Behavioral Neurosciences 2016
- Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. Neuropharmacology May 1, 2020
- Current perspectives on psychedelic therapy: use of serotonergic hallucinogens in clinical interventions International Review of Psychiatry July 4, 2018
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and 20 more in the library