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Pharmacology & Chemistry

Metabolism of lysergic acid diethylamide (LSD): an update.

July 16, 2019 / LSD, Papers, Pharmacology & Chemistry, Psychology, Publications / By /

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.
Libânio Osório Marta, R. F. (2019). Metabolism of lysergic acid diethylamide (LSD): an update. Drug metabolism reviews, 51(3), 378-387. https://doi.org/10.1080/03602532.2019.1638931
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Spectral signatures of serotonergic psychedelics and glutamatergic dissociatives

June 24, 2019 / LSD, Mushrooms / Psilocybin, Neuroscience, Papers, Pharmacology & Chemistry, Publications / By / , , , , , ,

Abstract

Classic serotonergic psychedelics are remarkable for their capacity to induce reversible alterations in consciousness of the self and the surroundings, mediated by agonism at serotonin 5-HT2A receptors. The subjective effects elicited by dissociative drugs acting as N-methyl-D-aspartate (NMDA) antagonists (e.g. ketamine and phencyclidine) overlap in certain domains with those of serotonergic psychedelics, suggesting some potential similarities in the brain activity patterns induced by both classes of drugs, despite different pharmacological mechanisms of action. We investigated source-localized magnetoencephalography recordings to determine the frequency-specific changes in oscillatory activity and long-range functional coupling that are common to two serotonergic compounds (lysergic acid diethylamide [LSD] and psilocybin) and the NMDA-antagonist ketamine. Administration of the three drugs resulted in widespread and broadband spectral power reductions. We established their similarity by using different pairs of compounds to train and subsequently evaluate multivariate machine learning classifiers. After applying the same methodology to functional connectivity values, we observed a pattern of occipital, parietal and frontal decreases in the low alpha and theta bands that were specific to LSD and psilocybin, as well as decreases in the low beta band common to the three drugs. Our results represent a first effort in the direction of quantifying the similarity of large-scale brain activity patterns induced by drugs of different mechanism of action, confirming the link between changes in theta and alpha oscillations and 5-HT2A agonism, while also revealing the decoupling of activity in the beta band as an effect shared between NMDA antagonists and 5-HT2A agonists. We discuss how these frequency-specific convergences and divergences in the power and functional connectivity of brain oscillations might relate to the overlapping subjective effects of serotonergic psychedelics and glutamatergic dissociative compounds.

Pallavicini, C., Vilas, M. G., Villarreal, M., Zamberlan, F., Muthukumaraswamy, S., Nutt, D., … & Tagliazucchi, E. (2019). Spectral signatures of serotonergic psychedelics and glutamatergic dissociatives. NeuroImage., 10.1016/j.neuroimage.2019.06.053
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Pharmacokinetics and subjective effects of a novel oral LSD formulation in healthy subjects.

April 29, 2019 / LSD, Neuroscience, Papers, Pharmacology & Chemistry / By / , , , , ,

Abstract

AIMS:

The aim of the present study was to characterize the pharmacokinetics and exposure-subjective response relationship of a novel oral solution of lysergic acid diethylamide (LSD) that was developed for clinical use in research and patients.

METHOD:

LSD (100 μg) was administered in 27 healthy subjects using a placebo-controlled, double-blind, cross-over design. Plasma levels of LSD, nor-LSD, and 2-oxo-3-hydroxy-LSD (O-H-LSD) and subjective drug effects were assessed up to 11.5 hours.

RESULTS:

First-order elimination kinetics were observed for LSD. Geometric mean maximum concentration (Cmax ) values (range) of 1.7 (1.0-2.9) ng/mL were reached at a tmax (range) of 1.7 (1.0-3.4) hours after drug administration. The plasma half-life (t1/2 ) was 3.6 (2.4-7.3) hours. The AUC∞ was 13 (7.1-28) ng·h/mL. No differences in these pharmacokinetic parameters were found between male and female subjects. Plasma O-H-LSD but not nor-LSD (< 0.01 ng/mL) concentrations could be quantified in all subjects. Geometric mean O-H-LSD Cmax values (range) of 0.11 (0.07-0.19) ng/mL were reached at a tmax (range) of 5 (3.2-8) hours. The t1/2 and AUC∞ values of O-H-LSD were 5.2 (2.6-21) hours and 1.7 (0.85-4.3) ng·h/mL, respectively. The subjective effects of LSD lasted (mean ± SD) for 8.5 ± 2.0 hours (range: 5.3-12.8 h), and peak effects were reached 2.5 ± 0.6 hours (range 1.6-4.3 h) after drug administration. EC50 values were 1.0 ± 0.5 ng/mL and 1.9 ± 1.0 ng/mL for “good” and “bad” subjective drug effects, respectively.

CONCLUSION:

The present study characterized the pharmacokinetics of LSD and its main metabolite O-H-LSD. The subjective effects of LSD were closely associated with changes in plasma concentrations over time.

Holze, F., Duthaler, U., Vizeli, P., Müller, F., Borgwardt, S., & Liechti, M. E. (2019). Pharmacokinetics and subjective effects of a novel oral LSD formulation in healthy subjects. British journal of clinical pharmacology., 10.1111/bcp.13918
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Cytochrome P450 enzymes contribute to the metabolism of LSD to nor-LSD and 2-oxo-3-hydroxy-LSD: Implications for clinical LSD use

April 11, 2019 / LSD, Neuroscience, Papers, Pharmacology & Chemistry / By / , , , ,

Abstract

In recent years, experimental research on lysergic acid diethylamide (LSD) in humans has gained new momentum. In humans, LSD is metabolized rapidly into several metabolites but knowledge of the involved metabolizing enzymes is limited. The aim of the current study was to identify the cytochrome P450 (CYP) isoforms involved in the metabolism of LSD to 6-norlysergic acid diethylamide (nor-LSD) and 2-oxo-3-hydroxy-LSD (O-H-LSD) in vitro, in order to evaluate potential effects of enzyme polymorphisms or prescription drugs on LSD pharmacokinetics. Additionally, interactions of LSD and both metabolites with 5-hydroxytryptamine (5-HT) receptors were assessed. LSD was incubated with human liver microsomes over 4 h and the production of nor-LSD and O-H-LSD was quantified by liquid chromatography tandem mass spectrometry. Metabolism was inhibited by the addition of specific CYP inhibitors. Additionally, recombinant CYPs were used to verify the inhibition results obtained with microsomes and induction of metabolism was investigated in human hepatocyte-derived cells. Radioligand binding and calcium mobilization assays were used to determine 5-HT receptor affinities and activities, respectively. Human liver microsomes displayed minor metabolite formation (<1% metabolized) over 4 h. CYP2D6, 2E1, and 3A4 significantly contributed to the formation of nor-LSD, and CYP1A2, 2C9, 2E1, and 3A4 were significantly involved in the formation of O-H-LSD. These findings could be verified using recombinant CYPs. Enzyme induction with rifampicin distinctly increased the formation of both metabolites, whereas treatment with omeprazole only slightly increased formation of nor-LSD. LSD and nor-LSD were pharmacologically active at the 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C receptors. Nor-LSD mainly differed from the parent compound by having a lower affinity to the 5-HT2C receptor. O-H-LSD displayed substantially weaker affinity and activity at serotonergic receptors in comparison to LSD. To conclude, human liver microsomes converted only small amounts of LSD to nor-LSD and O-H-LSD but several CYPs significantly contributed. Genetic polymorphisms and drug interactions could therefore influence pharmacokinetics and pharmacodynamics of LSD. Nor-LSD likely has hallucinogenic activity similar to LSD, whereas O-H-LSD is inactive. Drug-drug interaction studies in humans are required to further assess the clinical relevance of these findings.

Luethi, D., Hoener, M. C., Krähenbühl, S., Liechti, M. E., & Duthaler, U. (2019). Cytochrome P450 enzymes contribute to the metabolism of LSD to nor-LSD and 2-oxo-3-hydroxy-LSD: Implications for clinical LSD use. Biochemical pharmacology, 164, 129-138., 10.1016/j.bcp.2019.04.013
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Receptor-Enriched Analysis of functional connectivity by targets (REACT): A novel, multimodal analytical approach informed by PET to study the pharmacodynamic response of the brain under MDMA

April 4, 2019 / MDMA, Neuroscience, Papers, Pharmacology & Chemistry / By / , , , , ,

Abstract

One of the main limitations of pharmacological fMRI is its inability to provide a molecular insight into the main effect of compounds, leaving an open question about the relationship between drug effects and haemodynamic response. The aim of this study is to investigate the acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on functional connectivity (FC) using a novel multimodal method (Receptor-Enriched Analysis of functional Connectivity by Targets – REACT). This approach enriches the resting state (rs-)fMRI analysis with the molecular information about the distribution density of serotonin receptors in the brain, given the serotonergic action of MDMA. Twenty healthy subjects participated in this double-blind, placebo-controlled, crossover study. A high-resolution in vivo atlas of four serotonin receptors (5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4) and its transporter (5-HTT) was used as a template in a two-step multivariate regression analysis to estimate the spatial maps reflecting the whole-brain connectivity behaviour related to each target under placebo and MDMA. Results showed that the networks exhibiting significant changes after MDMA administration are the ones informed by the 5-HTT and 5-HT1Adistribution density maps, which are the main targets of this compound. Changes in the 5-HT1A-enriched functional maps were also associated with the pharmacokinetic levels of MDMA and MDMA-induced FC changes in the 5-HT2A-enriched maps correlated with the spiritual experience subscale of the Altered States of Consciousness Questionnaire. By enriching the rs-fMRI analysis with molecular data of voxel-wise distribution of the serotonin receptors across the brain, we showed that MDMA effects on FC can be understood through the distribution of its main targets. This result supports the ability of this method to characterise the specificity of the functional response of the brain to MDMA binding to serotonergic receptors, paving the way to the definition of a new fingerprint in the characterization of new compounds and potentially to a further understanding to the response to treatment.

Dipasquale, O., Selvaggi, P., Veronese, M., Gabay, A. S., Turkheimer, F., & Mehta, M. A. (2019). Receptor-Enriched Analysis of functional connectivity by targets (REACT): A novel, multimodal analytical approach informed by PET to study the pharmacodynamic response of the brain under MDMA. NeuroImage, 195, 252-260., 10.1016/j.neuroimage.2019.04.007

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Salvia divinorum: from recreational hallucinogenic use to analgesic and anti-inflammatory action

March 22, 2019 / Biology & Ethnobotany, Neuroscience, Papers, Pharmacology & Chemistry, Psychiatry & Medicine, Publications, Salvia / Salvinorin A / By / ,

Abstract

Salvia divinorum is a herbal plant native to the southwest region of Mexico. Traditional preparations of this plant have been used in illness treatments that converge with inflammatory conditions and pain. Currently, S. divinorum extracts have become popular in several countries as a recreational drug due to its hallucinogenic effects. Its main active component is a diterpene named salvinorin A (SA), a potent naturally occurring hallucinogen with a great affinity to the κ opioid receptors and with allosteric modulation of cannabinoid type 1 receptors. Recent biochemical research has revealed the mechanism of action of the anti-inflammatory and analgesic effect of SA at the cellular and molecular level. Nevertheless, because of their short-lasting and hallucinogenic effect, the research has focused on discovering a new analogue of SA that is able to induce analgesia and reduce inflammation with a long-lasting effect but without the hallucinatory component. In this review, we explore the role of S. divinorum, SA and its analogues. We focus mainly on their analgesic and anti-inflammatory roles but also mention their psychoactive properties.

Coffeen, U., & Pellicer, F. (2019). Salvia divinorum: from recreational hallucinogenic use to analgesic and anti-inflammatory action. Journal of pain research, 12, 1069., 10.2147/JPR.S188619

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Metabolite Profiling of Antiaddictive Alkaloids from Four Mexican Tabernaemontana Species and the Entheogenic African Shrub Tabernanthe iboga (Apocynaceae)

January 7, 2019 / Biology & Ethnobotany, Iboga / Ibogaine, Papers, Pharmacology & Chemistry, Publications, Substance Use Disorder / By / , , , ,

Abstract

Ibogaine and other ibogan type alkaloids present anti-addictive effects against several drugs of abuse and occur in different species of the Apocynaceae family. In this work, we used gas chromatography-mass spectrometry (GC/MS) and principal component analysis (PCA) in order to compare the alkaloid profiles of the root and stem barks of four Mexican Tabernaemontana species with the root bark of the entheogenic African shrub Tabernanthe iboga. PCA demonstrated that separation between species could be attributed to quantitative differences of the major alkaloids, coronaridine, ibogamine, voacangine, and ibogaine. While T. iboga mainly presented high concentrations of ibogaine, Tabernaemontana samples either showed a predominance of voacangine and ibogaine, or coronaridine and ibogamine, respectively. The results illustrate the phytochemical proximity between both genera and confirm previous suggestions that Mexican Tabernaemontana species are viable sources of anti-addictive compounds.

Krengel, F., Chevalier, Q., Dickinson, J., Santoyo, J. H., & Reyes-Chilpa, R. (2019). Metabolite Profiling of Antiaddictive Alkaloids from Four Mexican Tabernaemontana Species and the Entheogenic African Shrub Tabernanthe iboga (Apocynaceae). Chemistry & biodiversity., 10.1002/cbdv.201800506
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Monoamine biosynthesis via a noncanonical calcium-activatable aromatic amino acid decarboxylase in psilocybin mushroom

November 28, 2018 / Mushrooms / Psilocybin, Papers, Pharmacology & Chemistry, Publications / By / , , , ,

Abstract

Aromatic l-amino acid decarboxylases (AAADs) are a phylogenetically diverse group of enzymes responsible for the decarboxylation of aromatic amino acid substrates into their corresponding aromatic arylalkylamines. AAADs have been extensively studied in mammals and plants as they catalyze the first step in the production of neurotransmitters and bioactive phytochemicals, respectively. Unlike mammals and plants, the hallucinogenic psilocybin mushroom Psilocybe cubensis reportedly employs an unrelated phosphatidylserine-decarboxylase-like enzyme to catalyze l-tryptophan decarboxylation, the first step in psilocybin biosynthesis. To explore the origin of this chemistry in psilocybin mushroom, we generated the first de novo transcriptomes of P. cubensis and investigated several putative l-tryptophan-decarboxylase-like enzymes. We report the biochemical characterization of a noncanonical AAAD from P. cubensis (PcncAAAD) that exhibits substrate permissiveness toward l-phenylalanine, l-tyrosine, and l-tryptophan, as well as chloro-tryptophan derivatives. The crystal structure of PcncAAAD revealed the presence of a unique C-terminal appendage domain featuring a novel double-β-barrel fold. This domain is required for PcncAAAD activity and regulates catalytic rate and thermal stability through calcium binding. PcncAAAD likely plays a role in psilocybin production in P. cubensis and offers a new tool for metabolic engineering of aromatic-amino-acid-derived natural products.

Torrens-Spence, M. P., Liu, C. T., Pluskal, T., Chung, Y. K., & Weng, J. K. (2018). Monoamine Biosynthesis via a Noncanonical Calcium-Activatable Aromatic Amino Acid Decarboxylase in Psilocybin Mushroom. ACS chemical biology, 13(12), 3343-3353., 10.1021/acschembio.8b00821
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The Varieties of the Psychedelic Experience: A Preliminary Study of the Association Between the Reported Subjective Effects and the Binding Affinity Profiles of Substituted Phenethylamines and Tryptamines

November 8, 2018 / Neuroscience, Papers, Pharmacology & Chemistry, Publications / By / , , , , ,

Abstract

Classic psychedelics are substances of paramount cultural and neuroscientific importance. A distinctive feature of psychedelic drugs is the wide range of potential subjective effects they can elicit, known to be deeply influenced by the internal state of the user (“set”) and the surroundings (“setting”). The observation of cross-tolerance and a series of empirical studies in humans and animal models support agonism at the serotonin (5-HT)2A receptor as a common mechanism for the action of psychedelics. The diversity of subjective effects elicited by different compounds has been attributed to the variables of “set” and “setting,” to the binding affinities for other 5-HT receptor subtypes, and to the heterogeneity of transduction pathways initiated by conformational receptor states as they interact with different ligands (“functional selectivity”). Here we investigate the complementary (i.e., not mutually exclusive) possibility that such variety is also related to the binding affinity for a range of neurotransmitters and monoamine transporters including (but not limited to) 5-HT receptors. Building on two independent binding affinity datasets (compared to “in silico” estimates) in combination with natural language processing tools applied to a large repository of reports of psychedelic experiences (Erowid’s Experience Vaults), we obtained preliminary evidence supporting that the similarity between the binding affinity profiles of psychoactive substituted phenethylamines and tryptamines is correlated with the semantic similarity of the associated reports. We also showed that the highest correlation was achieved by considering the combined binding affinity for the 5-HT, dopamine (DA), glutamate, muscarinic and opioid receptors and for the Ca+ channel. Applying dimensionality reduction techniques to the reports, we linked the compounds, receptors, transporters and the Ca+ channel to distinct fingerprints of the reported subjective effects. To the extent that the existing binding affinity data is based on a low number of displacement curves that requires further replication, our analysis produced preliminary evidence consistent with the involvement of different binding sites in the reported subjective effects elicited by psychedelics. Beyond the study of this particular class of drugs, we provide a methodological framework to explore the relationship between the binding affinity profiles and the reported subjective effects of other psychoactive compounds.

Zamberlan, F., Sanz, C., Martinez Vivot, R., Pallavicini, C., Erowid, E., & Tagliazucchi, E. (2018). The varieties of the psychedelic experience: a preliminary study of the association between the reported subjective effects and the binding affinity profiles of substituted phenethylamines and tryptamines. Frontiers in integrative neuroscience, 12, 54., 10.3389/fnint.2018.00054.
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Iterative l-Tryptophan Methylation in Psilocybe Evolved by Subdomain Duplication

August 11, 2018 / Biology & Ethnobotany, Mushrooms / Psilocybin, Neuroscience, Papers, Pharmacology & Chemistry, Publications / By / , , , ,

Abstract

Psilocybe mushrooms are best known for their l-tryptophan-derived psychotropic alkaloid psilocybin. Dimethylation of norbaeocystin, the precursor of psilocybin, by the enzyme PsiM is a critical step during the biosynthesis of psilocybin. However, the “magic” mushroom Psilocybe serbica also mono- and dimethylates l-tryptophan, which is incompatible with the specificity of PsiM. Here, a second methyltransferase, TrpM, was identified and functionally characterized. Mono- and dimethylation activity on l-tryptophan was reconstituted in vitro, whereas tryptamine was rejected as a substrate. Therefore, we describe a second l-tryptophan-dependent pathway in Psilocybe that is not part of the biosynthesis of psilocybin. TrpM is unrelated to PsiM but originates from a retained ancient duplication event of a portion of the egtDB gene that encodes an ergothioneine biosynthesis enzyme. During mushroom evolution, this duplicated gene was widely lost but re-evolved sporadically and independently in various genera. We propose a new secondary metabolism evolvability mechanism, in which weakly selected genes are retained through preservation in a widely distributed, conserved pathway.

Blei, F., Fricke, J., Wick, J., Slot, J. C., & Hoffmeister, D. (2018). Iterative l‐Tryptophan Methylation in Psilocybe Evolved by Subdomain Duplication. ChemBioChem, 19(20), 2160-2166., 10.1002/cbic.201800336.
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