Simon D. Brandt

1‐Acetyl‐ N , N ‐diethyllysergamide (1A‐LSD, ALD‐52) was first synthesized in the 1950s and found to produce psychedelic effects similar to those of LSD. Evidence suggests that ALD‐52 serves as a prodrug in vivo and hydrolysis to LSD is likely responsible for its activity. Extension of the N 1 ‐alkylcarbonyl chain gives rise to novel lysergamides, which spurred further investigations into their structure–activity relationships. At the same time, ALD‐52 and numerous homologues have emerged as recreational drugs (“research chemicals”) that are available from online vendors. In the present study, 1‐dodecanoyl‐LSD (1DD‐LSD), a novel N 1 ‐acylated LSD derivative, was subjected to analytical characterization and was also tested in the mouse head‐twitch response (HTR) assay to assess whether it produces LSD‐like effects in vivo. When tested in C57BL/6J mice, 1DD‐LSD induced the HTR with a median effective dose (ED 50 ) of 2.17 mg/kg, which was equivalent to 3.60 μmol/kg. Under similar experimental conditions, LSD has 27‐fold higher potency than 1DD‐LSD in the HTR assay. Previous work has shown that other homologues such as ALD‐52 and 1‐propanoyl‐LSD also have considerably higher potency than 1DD‐LSD in mice, which suggests that hydrolysis of the 1‐dodecanoyl moiety may be comparatively less efficient in vivo. Further investigations are warranted to determine whether the increased lipophilicity of 1DD‐LSD causes it to be sequestered in fat, thereby reducing its exposure to enzymatic hydrolysis in plasma and tissues. Further clinical studies are also required to assess its activity in humans and to test the prediction that it could potentially serve as a long‐acting prodrug for LSD.

Preclinical investigations have shown that N ‐ethyl‐ N ‐isopropyllysergamide (EIPLA) exhibits lysergic acid diethylamide (LSD)‐like properties, which suggests that it might show psychoactive effects in humans. EIPLA is also an isomer of N 6 ‐ethylnorlysergic acid N , N ‐diethylamide (ETH‐LAD), a lysergamide known to produce psychedelic effects in humans that emerged as a research chemical. EIPLA was subjected to analysis by various forms of mass spectrometry, chromatography (GC, LC), nuclear magnetic resonance (NMR) spectroscopy, and GC condensed‐phase infrared spectroscopy. The most straightforward differentiation between EIPLA and ETH‐LAD included the evaluation of mass spectral features that reflected the structural differences (EIPLA: N 6 ‐methyl and N ‐ethyl‐ N ‐isopropylamide group; ETH‐LAD: N 6 ‐ethyl and N , N ‐diethylamide group). Proton NMR analysis of blotter extracts suggested that EIPLA was detected as the base instead of a salt, and two blotter extracts suspected to contain EIPLA revealed the detection of 96.9 ± 0.5 μg (RSD: 0.6%) and 85.8 ± 2.8 μg base equivalents based on LC–MS analysis. The in vivo activity of EIPLA was evaluated using the mouse head‐twitch response (HTR) assay. Similar to LSD and other serotonergic psychedelics, EIPLA induced the HTR (ED 50 = 234.6 nmol/kg), which was about half the potency of LSD (ED 50 = 132.8 nmol/kg). These findings are consistent with the results of previous studies demonstrating that EIPLA can mimic the effects of known psychedelic drugs in rodent behavioral models. The dissemination of analytical data for EIPLA was deemed justifiable to aid future forensic and clinical investigations.