In a November 2019 study published in Neuropharmacology, researchers tested whether the LSD (lysergic acid diethylamide) derivatives ALD-52 (1-acetyl-LSD), 1P-LSD (1-propanoyl-LSD), and 1B-LSD (1-butanoyl-LSD) are active compounds or prodrugs of LSD.1
The study used a three-pronged approach for testing the LSD derivatives: competitive binding studies and calcium mobilization to examine the interaction with serotonin receptors, head twitch response (HTR) studies in mice to assess in vivo activation of serotonin 5-HT2A receptor, and LC/MS (liquid chromatography/ion trap mass spectrometry) to quantify the amount of LSD in the blood of rats treated with two of the three derivatives.
The binding affinity data indicated that the 1-acyl substitution on the LSD derivatives reduced their affinity for 5-HT1A compared to LSD. The magnitude of the effect depended on the length of the acyl group. For 5-HT2A, an acetyl or propanoyl group on LSD’s indole nitrogen reduced receptor affinity by more than 10-fold compared to LSD. Substitution with a butanoyl group reduced affinity around 5-fold. Interestingly, the 1-acetyl substitutions increased the affinity of the derivatives at 5-HT2C by about 2-4-fold compared to LSD.
The data showed that ALD-52, 1P-LSD, and 1B-LSD were very weak partial agonists at the human 5-HT2A compared to LSD. Interestingly, despite showing comparatively high affinity for 5-HT2B and 5-HT2C, the compounds showed no agonist activity at those receptors. This behavior is in contrast to LSD, which is an agonist at recombinant human 5-HT2B and 5-HT2C receptors.
Although the data indicated the 1-acyl substitution on the derivatives reduced their affinity and efficacy at 5-HT2A, ALD-52, 1P-LSD, and 1B-LSD still induced head twitches in mice and showed a relatively high potency compared to other hallucinogens.
The authors reported that the LC/MS analysis indicated, “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.”