Prodrugs of New Psychoactive Substances (NPS): A New Challenge

Abstract

The concept of a substance acting as a prodrug for an intended drug is not new and has been known and utilized with particular benefits within medicine for efficacy and patient safety. Prodrugs of psychoactive substances are also not particularly new but this has also extended to considerations of prodrugs of new psychoactive substances (NPS). The continuing evolution of NPS has been a constant forensic challenge. In some countries, this constant evolution has led to the introduction of various alternative methods of drug control. Whether for this reason or in the pursuit of user experimentation, prodrugs of NPS have been discussed, developed, and exploited, posing some distinct forensic challenges. This is especially the case within toxicological analysis of biological fluids and for some substances, also forensic chemical analysis, through inherent instability of the prodrug or metabolism in the body. Particular examples of NPS prodrugs include 1-propanoyl-LSD, 1-butanoyl-LSD, 1-acetyl-LSD, and 2C-B-AN. This is in addition to associated substances and medicines that may be used for an intended pharmacological effect. Various prodrugs for stimulant and hallucinogenic substances in particular have appeared in the literature and have been discussed within drug user forums and made available for purchase online. Presently, drug monitoring data from national and international systems indicate that prodrugs are not widely available or problematic. Nevertheless, it is important that there is sufficient awareness of the prodrug concept and potential impact and associated forensic implications, not just for chemical analysis but also for toxicological considerations when a substance has been used.

Return of the lysergamides. Part VI: Analytical and behavioural characterization of 1‐cyclopropanoyl‐d‐lysergic acid diethylamide (1CP‐LSD)

“…These findings were also consistent with the data reported in an intoxication where the ingestion of 1P‐LSD in blotter form did not result in its detection in either urine or serum but LSD instead 23 . In the present investigation, an incubation of 1CP‐LSD with human serum also revealed the formation of LSD when the incubation mixture was analyzed by LC‐ESI single quadrupole MS. As summarized in the Supporting Information section (analyses performed in triplicate but only one representative example shown), it was found that the signal response related to the hydrolysis product increased over time when analyzed at 0, 1, 2, 3, 5, 7, and 24 h. These results showed that 1CP‐LSD was hydrolyzed to LSD in serum but that conversion was not complete within the first 24 h. However, 1CP‐LSD is likely to be hydrolyzed at a much faster rate in vivo because humans express carboxyesterase in red blood cell membranes but not in serum 37,38 . Indeed, 1P‐LSD has been shown to undergo relatively rapid hydrolysis in vivo.…”

“…showed that 1CP-LSD was hydrolyzed to LSD in serum but that conversion was not complete within the first 24 h. However, 1CP-LSD is likely to be hydrolyzed at a much faster rate in vivo because humans express carboxyesterase in red blood cell membranes but not in serum. 37,38 Indeed, 1P-LSD has been shown to undergo relatively rapid hydrolysis in vivo. In rats, high levels of LSD are found in the plasma 15 min after subcutaneous administration of ALD-52 and 1P-LSD, indicating they likely undergo rapid hydrolysis.…”

An insight into the metabolism of New Psychoactive Substances : Structural elucidation of urinary metabolites of synthetic cannabinoids and fentanyl analogues using synthesized reference standards

“…However, metabolites can conceivably contribute to the pharmacological effects of their parent drug. 210,211 An example of a parent drug with an active metabolite is oxycodone, another µ-opioid receptor agonist, which can be metabolized to oxymorphone mediated by the CYP2D6 enzyme ( Figure 15). 212 Oxymorphone is itself active at the µ-opioid receptor and listed under the 1961 Single Convention on Narcotic Drugs.…”

The detection and determination of new LSD derivatives in biological material using the LC-MS/MS technique

“…Derivatives substituted with an acyl group at the N 1 position show less potency than the parent compound. Their affinity for monoamine receptors, mainly dopaminergic or serotoninergic, including 5-HT 2A , which is the most important for the effect of LSD, is lower (Halberstadt et al, 2019;Brandt et al, 2020;Elliott, Holdbrook, Brandt, 2020). Homologues of LSD with substituents in the N 6 position can show a greater potency in the case of ethyl, n-propyl, or allyl substituents or a lesser potency in the case of longer substituents, such as the n-butyl group or the isopropyl group.…”

“…it should be noted, however, that there have been considerably fewer studies of the effects of LSD derivatives than of LSD itself (Brandt et al, 2017). Compounds with a modified structure in the N 1 position are rapidly hydrolysed to LSD in the body (Brandt et al, 2020;Elliott et al, 2020;Grumann et al, 2020). 1P-ETH-LAD metabolises to ETH-LAD (Brandt et al, 2017;Brandt et al, 2020;Elliott et al, 2020), which makes it difficult to identify in the biological material the psychoactive substance administered -as the parent substance may go undetected.…”