OPEN Foundation

Toxicology

LSD, My Problem Child

LSD, My Problem Child. Albert Hofmann. Oxford University Press. ISBN: 978-0198840206

In a highly candid and personal account, the father of LSD details the history of his “problem child” and his long and fruitful career as a research chemist. An essential read for anyone wanting to learn about how LSD originated and Hofmann’s view on its transition to recreational use.

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Psilocybin Mushrooms of the World: An Identification Guide

Psilocybin Mushrooms of the World: An Identification Guide. Paul Stamets. Ten Speed Press. ISBN: 978-0898158397

Detailed descriptions and color photographs for over 100 psilocybin-containing mushroom species are provided, as well as an exploration of their long-standing (and often religious) use by ancient peoples and their continued significance to modern-day culture.

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Post-Marketing Safety Concerns with Esketamine: A Disproportionality Analysis of Spontaneous Reports Submitted to the FDA Adverse Event Reporting System

Abstract

Introduction: Esketamine nasal spray received approval for treatment-resistant depression in March 2019.

Objective: Using the FDA Adverse Event Reporting System (FAERS) database (March 2019-March 2020), we analysed esketamine-related adverse events (AEs) to detect and characterize relevant safety signals.

Methods: We used the consolidated case/non-case approach to estimate the reporting odds ratio (ROR) and information component (IC) with relevant confidence intervals (95% CI) for esketamine-related AEs with ≥4 counts. Comparisons between serious and non-serious AEs were performed using non-parametric tests.

Results: The FAERS database contained 962 cases of esketamine-related AEs, with signals detected for several AEs, such as dissociation (ROR = 1,612.64, 95% CI = 1,354.63, 1,919.79; IC = 8.19, 95% CI = 7.96, 8.35), sedation (ROR = 238.46, 95% CI = 202.98, 280.15; IC = 7, 95% CI = 6.75, 7.18), feeling drunk (ROR = 96.17, 95% CI = 61.42, 150.57; IC = 4.84, 95% CI = 4.09, 5.36), suicidal ideation (ROR = 24.03, 95% CI = 18.72, 30.84; IC = 4.31, 95% CI = 3.9, 4.61), and completed suicide (ROR = 5.75, 95% CI = 3.18, 10.41; IC = 2.25, 95% CI = 1.23, 2.94). Signals for suicidal and self-injurious ideation, but not suicide attempt and completed suicide, remained when comparing esketamine to venlafaxine. Females and patients receiving antidepressant polypharmacy, co-medication with mood stabilizers, antipsychotics, benzodiazepines, or somatic medications were more likely to suffer from serious versus non-serious AEs (χ2 = 125.29, p < 0.001, χ2 = 9.08, p = 0.003, χ2 = 8.14, p = 0.004, χ2 = 19.48, p < 0.001, χ2 = 25.62, p < 0.001, and χ2 = 16.79, p < 0.001, respectively).

Conclusions: Esketamine may carry a clear potential for serious AEs, which deserves urgent clarification by means of further prospective studies.

Gastaldon, C., Raschi, E., Kane, J. M., Barbui, C., & Schoretsanitis, G. (2021). Post-marketing safety concerns with esketamine: a disproportionality analysis of spontaneous reports submitted to the FDA adverse event reporting system. Psychotherapy and psychosomatics90(1), 41-48; 10.1159/000510703
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Evaluation of the Cytotoxicity of Ayahuasca Beverages

Abstract

Ayahuasca is a beverage consumed at shamanic ceremonies and currently has gained popularity on recreational scenarios. It contains beta-carboline alkaloids and N,N-dimethyltryptamine, which possesses hallucinogenic effects. Only a few studies have elicited the psychoactive effects and the dose of such compounds on neurological dopaminergic cells or animals. In this work, we aimed to study the cytotoxic effects of these compounds present in ayahuasca beverages and on five different teas (Banisteriopsis caapi, Psychotria viridis, Peganum harmala, Mimosa tenuiflora and Dc Ab (commercial name)) preparations on dopaminergic immortalized cell lines. Moreover, a characterization of the derivative alkaloids was also performed. All the extracts were characterized by chromatographic systems and the effect of those compounds in cell viability and total protein levels were analyzed in N27 dopaminergic neurons cell line. This is the first article where cytotoxicity of ayahuasca tea is studied on neurological dopaminergic cells. Overall, results showed that both cell viability and protein contents decreased when cells were exposed to the individual compounds, as well as to the teas and to the two mixtures based on the traditional ayahuasca beverages.

Simão, A. Y., Gonçalves, J., Gradillas, A., García, A., Restolho, J., Fernández, N., Rodilla, J. M., Barroso, M., Duarte, A. P., Cristóvão, A. C., & Gallardo, E. (2020). Evaluation of the Cytotoxicity of Ayahuasca Beverages. Molecules (Basel, Switzerland), 25(23), 5594. https://doi.org/10.3390/molecules25235594

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Kinetic profile of N,N-dimethyltryptamine and β-carbolines in saliva and serum after oral administration of ayahuasca in a religious context

Ayahuasca is a beverage obtained from Banisteriopsis caapi plus Psychotria viridis. B. caapi contains the β-carbolines harmine, harmaline, and tetrahydroharmine that are monoamine oxidase inhibitors and P. viridis contains N,N-dimethyltryptamine (DMT) that is responsible for the visionary effects of the beverage. Ayahuasca use is becoming a global phenomenon, and the recreational use of DMT and similar alkaloids has also increased in recent years; such uncontrolled use can lead to severe intoxications. In this investigation, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to study the kinetics of alkaloids over a 24 h period in saliva and serum of 14 volunteers who consumed ayahuasca twice a month in a religious context. We compared the area under the curve (AUC), maximum concentration (Cmax ), time to reach Cmax (Tmax ), mean residence time (MRT), and half-life (t1/2 ), as well as the serum/saliva ratios of these parameters. DMT and β-carboline concentrations (Cmax ) and AUC were higher in saliva than in serum and the MRT was 1.5-3.0 times higher in serum. A generalized estimation equations (GEEs) model suggested that serum concentrations could be predicted by saliva concentrations, despite large individual variability in the saliva and serum alkaloid concentrations. The possibility of using saliva as a biological matrix to detect DMT, β-carbolines, and their derivatives is very interesting because it allows fast noninvasive sample collection and could be useful for detecting similar alkaloids used recreationally that have considerable potential for intoxication.

Lanaro, R., Mello, S. M., da Cunha, K. F., Silveira, G., Corrêa-Neto, N. F., Hyslop, S., Cabrices, O. G., Costa, J. L., & Linardi, A. (2021). Kinetic profile of N,N-dimethyltryptamine and β-carbolines in saliva and serum after oral administration of ayahuasca in a religious context. Drug testing and analysis, 13(3), 664–678. https://doi.org/10.1002/dta.2955

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Toxicokinetics and Toxicodynamics of Ayahuasca Alkaloids N, N-Dimethyltryptamine (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact

Abstract

Ayahuasca is a hallucinogenic botanical beverage originally used by indigenous Amazonian tribes in religious ceremonies and therapeutic practices. While ethnobotanical surveys still indicate its spiritual and medicinal uses, consumption of ayahuasca has been progressively related with a recreational purpose, particularly in Western societies. The ayahuasca aqueous concoction is typically prepared from the leaves of the N,N-dimethyltryptamine (DMT)-containing Psychotria viridis, and the stem and bark of Banisteriopsis caapi, the plant source of harmala alkaloids. Herein, the toxicokinetics and toxicodynamics of the psychoactive DMT and harmala alkaloids harmine, harmaline and tetrahydroharmine, are comprehensively covered, particularly emphasizing the psychological, physiological, and toxic effects deriving from their concomitant intake. Potential therapeutic utility, particularly in mental and psychiatric disorders, and forensic aspects of DMT and ayahuasca are also reviewed and discussed. Following administration of ayahuasca, DMT is rapidly absorbed and distributed. Harmala alkaloids act as potent inhibitors of monoamine oxidase A (MAO-A), preventing extensive first-pass degradation of DMT into 3-indole-acetic acid (3-IAA), and enabling sufficient amounts of DMT to reach the brain. DMT has affinity for a variety of serotonergic and non-serotonergic receptors, though its psychotropic effects are mainly related with the activation of serotonin receptors type 2A (5-HT2A). Mildly to rarely severe psychedelic adverse effects are reported for ayahuasca or its alkaloids individually, but abuse does not lead to dependence or tolerance. For a long time, the evidence has pointed to potential psychotherapeutic benefits in the treatment of depression, anxiety, and substance abuse disorders; and although misuse of ayahuasca has been diverting attention away from such clinical potential, research onto its therapeutic effects has now strongly resurged.

Brito-da-Costa, A. M., Dias-da-Silva, D., Gomes, N., Dinis-Oliveira, R. J., & Madureira-Carvalho, Á. (2020). Toxicokinetics and Toxicodynamics of Ayahuasca Alkaloids N,N-Dimethyltryptamine (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact. Pharmaceuticals (Basel, Switzerland), 13(11), 334. https://doi.org/10.3390/ph13110334

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The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3,4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats

Abstract

Rationale: The nonmedical use of new psychoactive substances (NPS) is a worldwide public health concern. The so-called “benzofury” compounds, 5-(2-aminopropyl)benzofuran (5-APB) and 6-(2-aminopropyl)benzofuran (6-APB), are NPS with stimulant-like properties in human users. These substances are known to interact with monoamine transporters and 5-HT receptors in transfected cells, but less is known about their effects in animal models.

Methods: Here, we used in vitro monoamine transporter assays in rat brain synaptosomes to characterize the effects of 5-APB and 6-APB, together with their N-methyl derivatives 5-MAPB and 6-MAPB, in comparison with 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA). In vivo neurochemical and behavioral effects of 5-APB (0.3 and 1.0 mg/kg, i.v.) and 6-APB (0.3 and 1.0 mg/kg, i.v.) were assessed in comparison with MDA (1.0 and 3.0 mg/kg, i.v.) using microdialysis sampling in the nucleus accumbens of conscious male rats.

Results: All four benzofuran derivatives were substrate-type releasers at dopamine transporters (DAT), norepinephrine transporters (NET), and serotonin transporters (SERT) with nanomolar potencies, similar to the profile of effects produced by MDA and MDMA. However, the benzofurans were at least threefold more potent than MDA and MDMA at evoking transporter-mediated release. Like MDA, both benzofurans induced dose-related elevations in extracellular dopamine and serotonin in the brain, but benzofurans were more potent than MDA. The benzofuran derivatives also induced profound behavioral activation characterized by forward locomotion which lasted for at least 2 h post-injection.

Conclusions: Overall, benzofurans are more potent than MDA in vitro and in vivo, producing sustained stimulant-like effects in rats. These data suggest that benzofuran-type compounds may have abuse liability and could pose risks for adverse effects, especially if used in conjunction with abused drugs or medications which enhance monoamine transmission in the brain.

Brandt, S. D., Walters, H. M., Partilla, J. S., Blough, B. E., Kavanagh, P. V., & Baumann, M. H. (2020). The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3, 4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats. Psychopharmacology237(12), 3703-3714; 10.1007/s00213-020-05648-z

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Exposure-Response Analysis to Assess the Concentration-QTc Relationship of Psilocybin/Psilocin

Abstract

Psilocybin is being developed for treating major depressive disorder. Psilocybin is readily dephosphorylated to psilocin upon absorption. The potential for psilocin proarrhythmic effect was assessed using a concentration-QTc interval (C-QTc) analysis from an open-label single ascending dose study of psilocybin. Psilocybin doses ranged from 0.3 to 0.6 mg/kg. This trial showed a significant but shallow C-QTc relationship. At the clinical dose of 25 mg, the mean psilocin maximum concentration is 18.7 ng/mL, and the associated mean (upper 90% confidence interval of mean) QTcF change is 2.1 (6.6) milliseconds. Given the short half-life of psilocin of about 4 hours, there would be no accumulation after monthly oral doses used in clinical trials. The upper limit of the 90% confidence interval of the model-predicted mean ΔQTcF crossed 10 milliseconds at a psilocin concentration of 31.1 ng/mL. At a supraclinical psilocin maximum concentration of about 60 ng/mL, ΔQTcF remains low, with a mean (upper limit of the 90% confidence interval) of 9.1 (17.9) milliseconds. This analysis enabled the characterization of the C-QTc relationship and prediction of QTc prolongation at the expected clinical and possible higher psilocybin doses.

Dahmane, E., Hutson, P. R., & Gobburu, J. V. (2020). Exposure‐Response Analysis to Assess the Concentration‐QTc Relationship of Psilocybin/Psilocin. Clinical Pharmacology in Drug Development.; 10.1002/cpdd.796

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In vivo effects of 3,4-methylenedioxymethamphetamine (MDMA) and its deuterated form in rodents: Drug discrimination and thermoregulation.

Abstract

BACKGROUND:

Recent clinical studies support the use of 3,4-methylenedioxymethamphetamine (MDMA) as an adjunct treatment for posttraumatic stress disorder (PTSD). Despite these promising findings, MDMA administration in controlled settings can increase blood pressure, heart rate, and body temperature. Previous studies indicate thatO-demethylated metabolites of MDMA contribute to its adverse effects. As such, limiting the conversion of MDMA to reactive metabolites may mitigate some of its adverse effects and potentially improve its safety profile for therapeutic use.

METHODS:

We compared the interoceptive and hyperthermic effects of a deuterium-substituted form of MDMA (d2-MDMA) to MDMA using rodent drug discrimination and biotelemetry procedures, respectively.

RESULTS:

Compared to MDMA, d2-MDMA produced full substitution for a 1.5 mg/kg MDMA training stimulus with equal potency and effectiveness in the drug discrimination experiment. In addition, d2-MDMA produced increases in body temperature that were shorter-lasting and of lower magnitude compared to equivalent doses of MDMA. Last, d2-MDMA and MDMA were equally effective in reversing the hypothermic effects of the selective 5-HT2A/2C antagonist ketanserin.

CONCLUSION:

These findings indicate that deuterium substitution of hydrogen at the methylenedioxy ring moiety does not impact MDMA’s interoceptive effects, and compared to MDMA, d2-MDMA has less potential for producing hyperthermic effects and likely has similar pharmacodynamic properties. Given that d2-MDMA produces less adverse effects than MDMA, but retains similar desirable effects that are thought to relate to the effective treatment of PTSD, additional investigations into its effects on cardiovascular functioning and pharmacokinetic properties are warranted.

Berquist, M. D., Leth-Petersen, S., Kristensen, J. L., & Fantegrossi, W. E. (2020). In vivo effects of 3, 4-methylenedioxymethamphetamine (MDMA) and its deuterated form in rodents: drug discrimination and thermoregulation. Drug and Alcohol Dependence, 107850., 10.1016/j.drugalcdep.2020.107850
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Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species

Abstract

Serotonergic hallucinogens such as lysergic acid diethylamide (LSD) induce head twitches in rodents via 5-HT2A receptor activation. The goal of the present investigation was to determine whether a correlation exists between the potency of hallucinogens in the mouse head-twitch response (HTR) paradigm and their reported potencies in other species, specifically rats and humans. Dose-response experiments were conducted with phenylalkylamine and tryptamine hallucinogens in C57BL/6J mice, enlarging the available pool of HTR potency data to 41 total compounds. For agents where human data are available (n = 36), a strong positive correlation (r = 0.9448) was found between HTR potencies in mice and reported hallucinogenic potencies in humans. HTR potencies were also found to be correlated with published drug discrimination ED50 values for substitution in rats trained with either LSD (r = 0.9484, n = 16) or 2,5-dimethoxy-4-methylamphetamine (r = 0.9564, n = 21). All three of these behavioral effects (HTR in mice, hallucinogen discriminative stimulus effects in rats, and psychedelic effects in humans) have been linked to 5-HT2A receptor activation. We present evidence that hallucinogens induce these three effects with remarkably consistent potencies. In addition to having high construct validity, the HTR assay also appears to show significant predictive validity, confirming its translational relevance for predicting subjective potency of hallucinogens in humans. These findings support the use of the HTR paradigm as a preclinical model of hallucinogen psychopharmacology and in structure-activity relationship studies of hallucinogens. Future investigations with a larger number of test agents will evaluate whether the HTR assay can be used to predict the hallucinogenic potency of 5-HT2A agonists in humans.

Halberstadt, A. L., Chatha, M., Klein, A. K., Wallach, J., & Brandt, S. D. (2020). Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. Neuropharmacology, 107933., 10.1016/j.neuropharm.2019.107933
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