Metabolism of lysergic acid diethylamide (LSD): an update

This review (2019) found that 2-oxo-3-hydroxy LSD was the major human metabolite of LSD. The inactive metabolite is detectable for longer than LSD.

Abstract

“Lysergic acid diethylamide (LSD) is the most potent hallucinogen known and its pharmacological effect results from stimulation of central serotonin receptors (5-HT2). Since LSD is seen as physiologically safe compound with low toxicity, its use in therapeutics has been renewed during the last few years. This review aims to discuss LSD metabolism, by presenting all metabolites as well as clinical and toxicological relevance. LSD is rapidly and extensively metabolized into inactive metabolites; whose detection window is higher than parent compound. The metabolite 2-oxo-3-hydroxy LSD is the major human metabolite, which detection and quantification is important for clinical and forensic toxicology. Indeed, information about LSD pharmacokinetics in humans is limited and for this reason, more research studies are needed.“

Author: Rui F. L. O. Marta

Summary

Lysergic acid diethylamide (LSD) is the most potent hallucinogen known and it stimulates central serotonin receptors (5-HT2). LSD is metabolized into inactive metabolites with a higher detection window than parent compound.

Introduction

Hallucinogens are psychoactive substances that induce states of altered perception, thought, and feeling. They can also cause users to feel out of control or disconnected from their body and environment.

Hallucinogenic substances are based on an agonist (or partial agonist) action at serotonin (5-HT)2A receptors, which explains their unique and powerful ability to affect the human psyche. They can cause two similar but distinct phenomena: flashbacks and Hallucinogen Persisting Perception Disorder.

LSD is a semi-synthetic compound derived from lysergic acid as found in fungus ergot Claviceps purpurea, which grows on rye. It is the most potent hallucinogen known and is used to induce psychedelic effects.

Recent studies have reintroduced the belief that psychedelics can be applied to the treatment of a variety of disorders, such as alcoholism and other addictions, anxiety and depression, schizophrenia, and even autism, obsessive-compulsive disorder, cluster headaches, and others.

Methodology

A literature research on LSD was carried out in PubMed, and then further reviewed to find additional publications.

Absorption and distribution

LSD is absorbed rapidly and completely in the gastrointestinal tract, and effects last 6 – 12h depending on dose. The amount of food consumed, the pH values of the stomach and duodenum, and the gastric evacuation rate affect absorption.

Aghajanian and Bing (1964) performed a small pharmacokinetic study and estimated a plasma elimination half-life of 175 min. The onset of symptoms varies according to the route of administration.

Two separate dose studies were conducted to determine the pharmacokinetic profile of LSD. Both doses presented a predicted mean half-life of 2.6 h and a mean duration of 8 and 11h, respectively, after administration of the 100- and 200-mg doses, respectively.

Pharmacokinetic studies in animals showed that 14C-labeled LSD is well absorbed and has a quick distribution into tissues, with the highest percentages in the liver, gut contents, plasma, lung, and liver.

As the drug penetrates the central nervous system, LSD brain concentration is expected. LSD binds extensively to plasma proteins at plasma concentrations of 0.1 and 20 mg/L.

There is some controversy about the relationship between LSD effects and LSD tissue concentration. Recently, Holze et al. (2019) found that plasma concentrations of LSD were not associated with the subjective effects of LSD.

Metabolism

There is still no fully defined metabolism of LSD, but it is assumed that LSD is extensively metabolized in liver tissue to structurally similar and inactive metabolites after N-dealkylation and/or oxidation processes. In humans, LSD undergoes metabolic N-demethylation at position 6 to form Nor-LSD.

Steuer et al. (2017) investigated the chemical structure of 13- or 14-hydroxy LSD metabolites in humans and identified a single peak corresponding to a hydroxy metabolite. They also indicated deethylation as the major metabolic route of LSD by human liver microsomes.

LSD is oxidized to 2-oxo-LSD, which undergoes subsequent hydroxylation to O-H-LSD. In addition to O-H-LSD, trioxylated-LSD and lysergic acid ethyl-2-hydroxy-ethylamide (LEO) may be present in human urine after an oxidation reaction and a dealkylation reaction, respectively.

Recently, Wagmann et al. (2019) identified several metabolites from LSD and LSD-based new psychoactive substances after in vitro studies with pooled human liver S9 fraction (pS9). The authors also studied the importance of monooxygenases to hepatic clearance.

LSD is metabolized by several CYPs, and genetic polymorphisms and drug interactions may affect LSD pharmacokinetics and pharmacodynamics. Moreover, recreational LSD use created new challenges for forensic and clinical toxicology.

Iso-LSD, a major contaminant in many illicit preparations, is detected in the urine and other body fluids of LSD users at higher concentrations than LSD. It has a longer elimination half-life than LSD.

Gomes et al. (2012) proposed a new metabolic pathway for LSD, which consists of the oxidation of LSD by peroxidases, and found that activated human neutrophils contain myeloperoxidase, which can oxidize LSD to O-H-LSD and Nor-LSD.

In vitro and in vivo studies have shown that LSD undergoes several alterations in animals, including N-demethylation, N-deethylation, aromatic hydroxylation, and oxidation at position 2. Cytochrome P450 plays an important role in LSD biotransformation.

Excretion

Only 1% of the dose of LSD is excreted in urine as unchanged LSD, and the concentrations range from 1.5 to 55 ng/mL. The urine of LSD users contains higher concentrations of 2-oxo-3-hydroxy-LSD relative to parent compound.

Rats excrete glucuronides of LSD mainly in the bile and feces, since the hydroxylated metabolites have a low lipid-solubility.

Considerations about applied analytical strategies for metabolite identification

LSD analysis is difficult due to the small doses involved, extensive metabolism, and volatility of the drug. Therefore, sensitive methods for measurement of LSD and its metabolite have been developed.

Various sample workup procedures have been tested, including liquid-liquid extraction (LLE), solid phase extraction (SPE), online extraction (Dolder, Liechti, et al. 2015), and protein precipitation (Dolder et al. 2018).

LSD can be quantified in brain tissue at concentrations up to 10.8 mg/kg, which is higher than in peripheral blood. Iso-LSD and O-H-LSD were also quantified, although in smaller amounts.

Conclusion and future perspectives

The popularity of hallucinogens has not been constant in the drug community over time, and the persistent use of these compounds can lead to serious psychologic consequences.

LSD is extensively metabolized into inactive metabolites and only very little of unchanged LSD is excreted. New metabolites can be detected in vitreous humor and hair of drug abusers, which can be helpful in forensic determination of postmortem LSD levels.