Metabolism of lysergic acid diethylamide (LSD): an update

Hallucinogens are psychoactive substances that produce altered perception, thought, and feeling at low doses without strong psychomotor stimulation. The introduction describes chemical classification (phenethylamines and tryptamines, which include ergolines such as LSD), typical acute somatic and perceptual effects, and rarer longer-term phenomena such as transient flashbacks and Hallucinogen Persisting Perception Disorder (HPPD). Unlike many other abused drugs, these compounds are generally considered to have low physiological toxicity and low dependence potential. Lysergic acid diethylamide (LSD) is presented as the prototypical ergoline, synthesised by Hofmann, highly potent at cortical 5-HT2A receptors, historically used experimentally and recreationally, and subject to renewed therapeutic interest for conditions including addiction, anxiety and depression. Filipe and colleagues state that the pharmacology of LSD remains incompletely characterised and that metabolic knowledge in humans is limited. The review therefore aims to compile and discuss available data on LSD metabolism, its metabolites, and the clinical and forensic relevance of those metabolites, emphasising gaps that warrant further research.

An extensive English-language literature search was performed in PubMed with no date restriction to identify articles on LSD and its metabolism. Full electronic copies of retrieved journal articles and relevant books were obtained and examined to locate additional publications covering both human and nonhuman studies. The methodology description is brief and does not list specific search terms, inclusion/exclusion criteria, study selection flow, or formal quality assessment procedures; it reports only that the retrieved literature and books were reviewed to assemble the metabolic data presented.

Absorption and distribution The review reports that oral administration is the most common route for LSD, with the extracted text stating an oral bioavailability of approximately 71% and absorption occurring within about 1 hour; subjective effects are reported to last 6–12 hours depending on dose. Food, gastric pH and gastric emptying modify absorption. Several human pharmacokinetic observations are summarised: an older small i.v. study (single 2 ug/kg doses in five healthy males) yielded plasma concentrations of about 6–7 ng/mL at 30 min after i.v., 4–6 ng/mL at 30–120 min, and ~1 ng/mL at 8 h, with an estimated plasma elimination half-life of 175 min. Oral studies cited include one with single 160 mg doses in 13 males showing peak plasma levels 40–130 min after dosing (peaks 1.8–8.8 ng/mL), and two more recent oral dose studies reporting median Tmax ~1.5 h, mean peak 1.3 ng/mL after 100 mg, higher peaks after 200 mg, and predicted mean half-lives of 2.6–3.6 h. The review emphasises a close temporal relationship between plasma concentrations and physiological response in some studies but notes other reports found no consistent correlation across subjects. Animal distribution data are presented to show rapid tissue uptake, with particularly high levels in liver (site of metabolism), kidney, spleen, brain, muscle and fat. LSD is said to cross the blood–brain barrier readily and has been detected in brain and cerebrospinal fluid across species. In vitro guinea‑pig data indicate extensive plasma protein binding (65–90%) at tested concentrations. A reported volume of distribution is low (0.28 L/kg) in the extracted text. Metabolism The investigators conclude that LSD is extensively metabolised and only about 1% of an administered dose is excreted unchanged in urine. Metabolic pathways described include N‑demethylation to N‑demethyl‑LSD (Nor‑LSD), N‑dealkylation to lysergic acid ethylamide (LAE) and other deethylated products, aromatic hydroxylation at positions 13 and 14, and oxidation at position 2 to form 2‑oxo‑LSD followed by further hydroxylation to 2‑oxo‑3‑hydroxy‑LSD (O‑H‑LSD). The review identifies O‑H‑LSD (2‑oxo‑3‑hydroxy‑LSD) as the major human metabolite, typically present at concentrations 16–43 times greater than parent LSD and detectable for a longer window (possibly days), making it the principal forensic/clinical marker of use. Phase II glucuronidation of hydroxylated metabolites is noted as an important detoxification and excretion pathway. Several metabolites have been detected in vitro using human liver microsomes, cryopreserved hepatocytes and pooled human liver S9 fractions; these include LAE, Nor‑LSD, mono‑ and di‑oxygenated and trioxylated species, and glucuronide conjugates. Enzymatic contributors identified include multiple cytochrome P450 isoforms: CYP3A4, CYP1A2 and CYP2C19 are highlighted for general LSD metabolism, with CYP2D6, CYP2E1 and CYP3A4 implicated in formation of Nor‑LSD, and CYP1A2, CYP2C9, CYP2E1 and CYP3A4 contributing to O‑H‑LSD formation. The review raises the prospect that genetic polymorphisms and drug–drug interactions affecting these enzymes could influence LSD pharmacokinetics and pharmacodynamics. Alternative metabolic mechanisms are discussed: peroxidase systems (horseradish peroxidase/H2O2 and myeloperoxidase in activated neutrophils) were able to oxidise LSD to metabolites observed in vivo, and produced additional products such as FOMBK and AOMBK. The text also addresses forensic complexity introduced by LSD derivatives and impurities: 1‑Propionyl‑LSD (1P‑LSD) may act as a prodrug; iso‑LSD is often present as a synthetic contaminant rather than a metabolic product and can be found at higher concentrations than LSD in some illicit preparations. Iso‑LSD is reported to have a longer elimination half-life (median 12 h) than LSD (median 4.2 h) according to the extracted text. Several metabolites including iso‑LSD, O‑H‑LSD, Nor‑LSD, LAE, LEO, 2‑oxo‑LSD and 13/14‑hydroxy‑LSD were detected in plasma samples from a controlled trial but often at levels too low for quantification. Excretion Only about 1% of an administered LSD dose is excreted unchanged in urine; urinary concentrations reported in the extracted text ranged from 1.5 to 55 ng/mL in specimens analysed after ingestion of 200 and 400 mg. O‑H‑LSD is present in urine at higher concentrations relative to parent LSD and can be detected for up to around 4 days. Glucuronide conjugation promotes renal excretion of hydroxylated metabolites. One study cited reported maximal urinary excretion occurring approximately 4–6 h after a 200 mg oral dose. In rats, LSD glucuronides are largely excreted in bile (nearly 80% of dose), and enterohepatic recirculation is limited because released hydroxylated metabolites are relatively hydrophilic. A renal clearance value of 1.32 ± 0.6 mL/min (approximately 1.6% of apparent total oral clearance) is presented in the extracted text. Analytical considerations The review highlights analytical challenges: low doses and extensive metabolism yield very low analyte concentrations in biological matrices; in addition, LSD is volatile, thermally labile and prone to adsorptive loss, complicating gas chromatographic analysis. Confirmatory techniques routinely used include GC‑MS and LC‑MS(/MS). Various sample preparation approaches have been trialled, including liquid–liquid extraction, solid‑phase extraction (with cation‑exchange sorbents such as HCX giving the required sensitivity), online extraction and protein precipitation. A microflow LC‑MS/MS method for plasma has been developed and validated but reported weaknesses in ruggedness. Brain tissue can contain higher concentrations than peripheral fluids and has been used in postmortem quantification. Stability data presented indicate LSD and key metabolites are relatively stable when frozen (reported stability at −20 °C and −80 °C for months), but degrade under ambient temperature, light, extreme pH or in presence of metals; conversion to iso‑LSD increases at room temperature. The authors recommend simultaneous analysis of parent and metabolites to extend the detection window and improve identification.

The authors conclude that LSD is extensively metabolised to inactive products and that only a small fraction of an administered dose is excreted unchanged. O‑H‑LSD emerges as the principal human metabolite and an important marker for clinical and forensic detection due to its higher concentrations and longer detection window than parent LSD. The review notes expanding analytical capability, including detection of LSD and metabolites in vitreous humour and hair, which may aid forensic investigations. Finally, Filipe and colleagues call for improved analytical sensitivity and further research into human pharmacokinetics, pharmacogenomics and drug interaction effects to better understand LSD metabolism and to support clinical and forensic applications.