Pharmacological and biotransformation studies of 1-acyl-substituted derivatives of -lysergic acid diethylamide (LSD)
Adam L. Halberstadt, Muhammad Chatha, Adam K. Klein, John D. Mccorvy, Markus R Meyer, Lea Wagmann, Alexander Stratford, Simon D. Brandt
Neuropharmacology November 19, 2019 DOI: 10.1016/j.neuropharm.2019.107856 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | C57BL/6J mice and Sprague-Dawley rats |
| Interventions | ALD-52 1P-LSD 1B-LSD |
| Topics | LSD Psilocybin Serotonin |
| Keywords | Pharmacology Hallucinogen Agonist Metabolite Receptor In vivo Stereochemistry Biochemistry |
| Citations | 37 |
| Key findings | 1-acyl-substituted LSD derivatives are rapidly deacylated in vivo to produce LSD, consistent with acting as prodrugs. |
Abstract
The ergoline d-lysergic acid diethylamide (LSD) is one of the most potent psychedelic drugs. 1-Acetyl-LSD (ALD-52), a derivative of LSD containing an acetyl group on the indole nitrogen, also produces psychedelic effects in humans and has about the same potency as LSD. Recently, several other 1-acyl-substitued LSD derivatives, including 1-propanoyl-LSD (1P-LSD) and 1-butanoyl-LSD (1B-LSD), have appeared as designer drugs. Although these compounds are assumed to act as prodrugs for LSD, studies have not specifically tested this prediction. The present investigation was conducted to address the gap of information about the pharmacological effects and mechanism-of-action of 1-acyl-substituted LSD derivatives. Competitive binding studies and calcium mobilization assays were performed to assess the interaction of ALD-52, 1P-LSD, and 1B-LSD with serotonin 5-HT2 receptor subtypes. A receptorome screening was performed with 1B-LSD to assess its binding to other potential targets. Head twitch response (HTR) studies were performed in C57BL/6J mice to assess in vivo activation of 5-HT2A (the receptor thought to be primarily responsible for hallucinogenesis). Finally, liquid chromatography/ion-trap mass spectrometry (LC/MS) was used to quantify plasma levels of LSD in Sprague-Dawley rats treated with ALD-52 and 1P-LSD. 1-Acyl-substitution reduced the affinity of LSD for most monoamine receptors, including 5-HT2A sites, by one to two orders of magnitude. Although LSD acts as an agonist at 5-HT2 subtypes, ALD-52, 1P-LSD and 1B-LSD have weak efficacy or act as antagonists in Ca2+-mobilization assays. Despite the detrimental effect of 1-acyl substitution on 5-HT2A affinity and efficacy, 1-acyl-substitued LSD derivatives induce head twitches in mice with relatively high potency. High levels of LSD were detected in the plasma of rats after subcutaneous administration of ALD-52 and 1P-LSD, demonstrating these compounds are rapidly and efficiently deacylated in vivo. These findings are consistent with the prediction that ALD-52, 1P-LSD and 1B-LSD serve as prodrugs for LSD. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.
Comparable studies
Other preclinical and animal studies on LSD, most cited first.
Citations in the library
Cited by 22
- Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms Pharmacological Reviews December 16, 2020
- Return of the lysergamides. Part V: Analytical and behavioural characterization of 1‐butanoyl‐d‐lysergic acid diethylamide (1B‐LSD) Drug Testing and Analysis May 13, 2019
- Return of the lysergamides. Part VI: Analytical and behavioural characterization of 1‐cyclopropanoyl‐d‐lysergic acid diethylamide (1CP‐LSD) Drug Testing and Analysis March 16, 2020
- Prodrugs of New Psychoactive Substances (NPS): A New Challenge. Journal of Forensic Sciences May 1, 2020
- Pharmacokinetics and subjective effects of 1P‐LSD in humans after oral and intravenous administration Drug Testing and Analysis May 16, 2020
and 17 more in the library
Cites 42
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- Structural Features for Functional Selectivity at Serotonin Receptors Science March 21, 2013
- Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials Journal of Psychopharmacology March 8, 2012
- Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels Neuropsychopharmacology January 26, 2019
- Crystal structure of an LSD-bound human serotonin receptor Cell January 26, 2017
and 37 more in the library