Publications by authors named "Matthias Liechti"

155 Publications

Characterizing thalamocortical (dys)connectivity following d-amphetamine, LSD, and MDMA administration.

Biol Psychiatry Cogn Neurosci Neuroimaging 2022 Apr 29. Epub 2022 Apr 29.

Translational Psychiatry, Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, 23538, Germany.

Background: Patients with psychotic disorders present alterations in thalamocortical intrinsic functional connectivity (iFC) as measured by resting-state functional magnetic resonance imaging (rs-fMRI). Specifically, thalamic iFC is increased with sensorimotor cortices (hyperconnectivity) and decreased with prefrontal-limbic cortices (hypoconnectivity). Intriguingly, psychedelics such as lysergic acid diethylamide (LSD) elicit similar thalamocortical-hyperconnectivity with sensorimotor areas in healthy volunteers. It is unclear whether LSD also induces thalamocortical-hypoconnectivity with prefrontal-limbic cortices as current findings are equivocal. Notably, thalamocortical-hyperconnectivity was associated with psychotic symptoms in patients and substance-induced altered states of consciousness in healthy volunteers. Thalamocortical dysconnectivity is likely evoked by altered neurotransmission, e.g., via dopaminergic excess in psychotic disorders and serotonergic agonism in psychedelic-induced states. It is unclear whether thalamocortical dysconnectivity is also elicited by amphetamine-type substances, broadly releasing monoamines (i.e., dopamine, norepinephrine) but producing fewer perceptual effects than psychedelics.

Methods: We administrated LSD, d-amphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) in 28 healthy volunteers and investigated their effects on thalamic iFC with two brain networks (auditory-sensorimotor (ASM) and salience (SAL) - corresponding to sensorimotor and prefrontal-limbic cortices, respectively), using a double-blind, placebo-controlled, cross-over design.

Results: All active substances elicited ASM-thalamic-hyperconnectivity compared to placebo, despite predominantly distinct pharmacological actions and subjective effects. LSD-induced effects correlated with subjective changes in perception, indicating a link between hyperconnectivity and psychedelic-type perceptual alterations. Unlike d-amphetamine and MDMA, which induced hypoconnectivity with SAL, LSD elicited hyperconnectivity. D-amphetamine and MDMA evoked similar thalamocortical dysconnectivity patterns.

Conclusions: Psychedelics, empathogens, and psychostimulants evoke thalamocortical-hyperconnectivity with sensorimotor areas, akin to findings in patients with psychotic disorders.
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http://dx.doi.org/10.1016/j.bpsc.2022.04.003DOI Listing
April 2022

Clinical effect of ethanol co-use in patients with acute drug toxicity involving the use of central nervous system depressant recreational drugs.

Eur J Emerg Med 2022 Apr 8. Epub 2022 Apr 8.

Division of Clinical Toxicology and Poison Control Centre Munich, Department of Internal Medicine II, TUM School of Medicine, Technical University of Munich, Germany.

Background And Importance: Patients who use recreational drugs frequently co-ingest ethanol, which is considered a central nervous system (CNS) depressant. The clinical relevance of this in acute toxicity involving other CNS depressants is not well described.

Objective: To assess the clinical impact of ethanol co-use in patients presenting to the emergency department (ED) with acute toxicity involving the use of CNS depressant drugs.

Design, Settings And Participants: A retrospective multicentre study using data from the Euro-DEN Plus database from January 2014 to December 2019.

Outcomes Measure And Analysis: Comparison of epidemiologic and clinical characteristics, ED and hospital management of patients with CNS depressant intoxication with or without ethanol co-use.

Main Results: Although 7644 (17.5%) of the 43 633 presentations were included, ethanol was co-ingested in 3811 (49.9%). In total 53.3% required medical treatment, 14 patients died. Patients with ethanol co-use more frequently presented with a Glasgow Coma Scale (GCS) ≤8 (34.1% vs. 22.4%; P  < 0.001), vomiting (8.1% vs. 4.6%; P  < 0.001), anxiety (12 % vs. 6.4%; P  < 0.001), agitation/aggression (22% vs. 14.7%; P  < 0.001), seizures (3.8% vs. 2.4%; P  < 0.001) and hypotension (7.5% vs. 4.6%; P  < 0.001). They more often required ambulance transport (85.5% vs. 76.5%; P  < 0.001), medical treatment (57.3% vs. 48.0%; P  < 0.001), hospitalization (27.7% vs. 18.9%; P  < 0.001), and admission to intensive care (12.2% vs. 4.0%; P  < 0.001). Subgroup analysis showed that GCS ≤8 was particularly common in patients who combined ethanol with opioids or gamma-hydroxybutyrate (GHB)/gamma-butyrolactone (GBL).

Conclusion: Co-use of ethanol with CNS-depressant drugs appears to increase the risk of adverse effects and is associated with a higher need for medical treatment, especially when ethanol is combined with opioids or GHB/GBL.
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http://dx.doi.org/10.1097/MEJ.0000000000000932DOI Listing
April 2022

Differences in clinical features associated with cannabis intoxication in presentations to European emergency departments according to patient age and sex.

Clin Toxicol (Phila) 2022 Apr 11:1-8. Epub 2022 Apr 11.

Emergency Department, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Catalonia, Spain.

Objective: To investigate if clinical features associated with acute cannabis intoxication in patients presenting to Emergency Departments for medical assistance differ according to patient age and sex.

Methods: We analysed presentations in the Euro-DEN Plus dataset from 2014 to 2019 in which cannabis was the only drug involved (except for alcohol), and age, sex and alcohol co-ingestion had been recorded. Age was considered as categorical (five groups; <20, 20-29, 30-39, 40-49 and ≥50 years), and sex as binary variable (male/female). We evaluated 12 key clinical features recorded during emergency department (ED) care. Risks of presenting with each of these clinical features according to patient age and sex were calculated by logistic regression models, and adjusted for sex, age and alcohol co-ingestion.

Results: 4,268 of 43,633 Euro-DEN presentations (9.8%) fulfilled the inclusion criteria (median age: 26 years (IQR = 20-34), 70% male, 52% co-ingested alcohol). The frequency of clinical features was: anxiety 28%, vomiting 24%, agitation 23%, palpitations 14%, reduced consciousness 13%, acute psychosis 9%, hallucinations 9%, chest pain 7%, headache 6%, hypotension 4%, hypertension 3% and seizures 2%. Patients younger than 20 years more frequently had vomiting (34.7% of cases), reduced consciousness (21.5%), and headache (10.8%); and less frequently acute psychosis (5.5%). Patients older than 49 years more often had hypotension (6.5%) and less frequently vomiting (20%), anxiety (14%), agitation (14%) and reduced consciousness (10%). Males more frequently presented with hypertension (3.7 vs. 1.5%; OR = 2.311, 95%CI = 1.299-3.816), psychosis (10.4 vs 6.3%; 1.948, 1.432-2.430), chest pain (8.1 vs 4.5%; 1.838, 1.390-2.430) and seizures (2.5 vs 1.4%; 1.805, 1.065-3.060), and less frequently with vomiting (21.8 vs 28.2%; 0.793, 0.677-0.930), anxiety (25.4 vs 32.3%; 0.655, 0.561-0.766) and hypotension (2.9 vs 5.8%; 0.485, 0.350-0.671).

Conclusions: The prevalence of some clinical features typically associated with acute cannabis intoxication differed according to age and sex. The causes for these differences should be further investigated in order to better understand the pathophysiology of cannabis-related acute toxicity, and they may be relevant particularly for developing prevention campaigns and for treatment in specific sex and/or age groups.
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http://dx.doi.org/10.1080/15563650.2022.2060116DOI Listing
April 2022

Pharmacological characterization of 3,4-methylenedioxyamphetamine (MDA) analogs and two amphetamine-based compounds: N,α-DEPEA and DPIA.

Eur Neuropsychopharmacol 2022 Jun 1;59:9-22. Epub 2022 Apr 1.

Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland; Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria.

3,4-methylenedioxyamphetamine (MDA) is a psychoactive compound chemically related to the entactogen MDMA. MDA shares some of the entactogenic effects of MDMA but also exerts stimulant effects and psychedelic properties at higher doses. Here, we examined the pharmacological properties of MDA analogs and related amphetamine-based compounds detected in street drug samples or in sport supplements. We examined the key pharmacological mechanisms including monoamine uptake inhibition and release using human embryonic kidney 293 cells stably transfected with the respective human transporters. Additionally, we assessed monoamine transporter and receptor binding and activation properties. MDA, its fluorinated analogs, as well as the α-ethyl containing BDB and the dimeric amphetamine DPIA inhibited NET with the greatest potency and preferentially inhibited 5-HT vs. dopamine uptake. The β‑methoxy MDA analog 3C-BOH and the amphetamine-based N,α-DEPEA inhibited NET and preferentially inhibited dopamine vs. 5-HT uptake. The test drugs mediated efflux of at least one monoamine with the exception of DPIA. Most compounds bound to 5-HT and 5-HT receptors (K ≤ 10 µM) and several substances activated the 5-HT and 5-HT receptor as partial or full agonists. Furthermore, several compounds interacted with adrenergic receptors and the trace amine-associated receptor 1 (TAAR1) in the micromolar range. The pharmacological profiles of some fluorinated and nonfluorinated MDA analogs resemble the profile of MDMA. In contrast, 3C-BOH and N,α-DEPEA displayed more pronounced dopaminergic activity similar to amphetamine. Pharmacokinetics and pharmacodynamics studies are necessary to better establish the risks and therapeutic potential of the tested drugs.
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http://dx.doi.org/10.1016/j.euroneuro.2022.03.006DOI Listing
June 2022

Corrigendum: Cell-Based Radiotracer Binding and Uptake Inhibition Assays: A Comparison of Methods to Assess the Potency of Drugs That Target Monoamine Transporters.

Front Pharmacol 2022 16;13:878641. Epub 2022 Mar 16.

Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.

[This corrects the article DOI: 10.3389/fphar.2020.00673.].
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http://dx.doi.org/10.3389/fphar.2022.878641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8966766PMC
March 2022

Correction to: Designer drugs: mechanism of action and adverse effects.

Arch Toxicol 2022 May;96(5):1489

Division of Clinical Pharmacology and Toxicology, University Hospital Basel and University of Basel, Schanzenstrasse 55, 4056, Basel, Switzerland.

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http://dx.doi.org/10.1007/s00204-022-03244-yDOI Listing
May 2022

Receptor Interaction Profiles of 4-Alkoxy-3,5-Dimethoxy-Phenethylamines (Mescaline Derivatives) and Related Amphetamines.

Front Pharmacol 2021 9;12:794254. Epub 2022 Feb 9.

Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland.

3,4,5-Trimethoxyphenethylamine (mescaline) is a psychedelic alkaloid found in peyote cactus. Related 4-alkoxy-3,5-dimethoxy-substituted phenethylamines (scalines) and amphetamines (3C-scalines) are reported to induce similarly potent psychedelic effects and are therefore potential novel therapeutics for psychedelic-assisted therapy. Herein, several pharmacologically uninvestigated scalines and 3C-scalines were examined at key monoamine targets . Binding affinity at human serotonergic 5-HT, 5-HT, and 5-HT, adrenergic α and α, and dopaminergic D receptors, rat and mouse trace amine-associated receptor 1 (TAAR1), and human monoamine transporters were assessed using target specific transfected cells. Furthermore, activation of human 5-HT and 5-HT receptors, and TAAR1 was examined. Generally, scalines and 3C-scalines bound with weak to moderately high affinity to the 5-HT receptor ( = 150-12,000 nM). 3C-scalines showed a marginal preference for the 5-HT vs the 5-HT and 5-HT receptors whereas no preference was observed for the scalines. Extending the 4-alkoxy substituent increased 5-HT and 5-HT receptors binding affinities, and enhanced activation potency and efficacy at the 5-HT but not at the 5-HT receptor. Introduction of fluorinated 4-alkoxy substituents generally increased 5-HT and 5-HT receptors binding affinities and increased the activation potency and efficacy at the 5-HT and 5-HT receptors. Overall, no potent affinity was observed at non-serotonergic targets. As observed for other psychedelics, scalines and 3C-scalines interacted with the 5-HT and 5-HT receptors and bound with higher affinities (up to 63-fold and 34-fold increase, respectively) when compared to mescaline.
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http://dx.doi.org/10.3389/fphar.2021.794254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8865417PMC
February 2022

Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects.

Neuropsychopharmacology 2022 05 25;47(6):1180-1187. Epub 2022 Feb 25.

Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Basel, Switzerland.

Growing interest has been seen in using lysergic acid diethylamide (LSD) and psilocybin in psychiatric research and therapy. However, no modern studies have evaluated differences in subjective and autonomic effects of LSD and psilocybin or their similarities and dose equivalence. We used a double-blind, randomized, placebo-controlled, crossover design in 28 healthy subjects (14 women, 14 men) who underwent five 25 h sessions and received placebo, LSD (100 and 200 µg), and psilocybin (15 and 30 mg). Test days were separated by at least 10 days. Outcome measures included self-rating scales for subjective effects, autonomic effects, adverse effects, effect durations, plasma levels of brain-derived neurotrophic factor (BDNF), prolactin, cortisol, and oxytocin, and pharmacokinetics. The doses of 100 and 200 µg LSD and 30 mg psilocybin produced comparable subjective effects. The 15 mg psilocybin dose produced clearly weaker subjective effects compared with both doses of LSD and 30 mg psilocybin. The 200 µg dose of LSD induced higher ratings of ego-dissolution, impairments in control and cognition, and anxiety than the 100 µg dose. The 200 µg dose of LSD increased only ratings of ineffability significantly more than 30 mg psilocybin. LSD at both doses had clearly longer effect durations than psilocybin. Psilocybin increased blood pressure more than LSD, whereas LSD increased heart rate more than psilocybin. However, both LSD and psilocybin showed comparable cardiostimulant properties, assessed by the rate-pressure product. Both LSD and psilocybin had dose-proportional pharmacokinetics and first-order elimination. Both doses of LSD and the high dose of psilocybin produced qualitatively and quantitatively very similar subjective effects, indicating that alterations of mind that are induced by LSD and psilocybin do not differ beyond the effect duration. Any differences between LSD and psilocybin are dose-dependent rather than substance-dependent. However, LSD and psilocybin differentially increased heart rate and blood pressure. These results may assist with dose finding for future psychedelic research.Trial registration: ClinicalTrials.gov identifier: NCT03604744.
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http://dx.doi.org/10.1038/s41386-022-01297-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9018810PMC
May 2022

Flashback phenomena after administration of LSD and psilocybin in controlled studies with healthy participants.

Psychopharmacology (Berl) 2022 Jun 25;239(6):1933-1943. Epub 2022 Jan 25.

Department of Psychiatry and Psychotherapy, University of Lübeck, 23538, Lübeck, Germany.

Background: LSD and psilocybin are increasingly used in phase I trials and evaluated as therapeutic agents for mental disorders. The phenomenon of reoccurring drug-like experiences after the acute substance effects have worn off was described for both substances and especially attributed to LSD. According to the DSM-V, the persisting and distressing manifestation of these experiences is called hallucinogen-persisting perception disorder (HPPD). Data on both conditions is very limited.

Objective: This study aims to provide descriptive data on reoccurring drug-like experiences after the administration of LSD and psilocybin in controlled studies with healthy participants.

Methods And Materials: Data from 142 healthy subjects enrolled in six double-blinded, placebo-controlled, randomized cross-over studies were analyzed. In total, 60 subjects received LSD; 27 subjects received LSD, MDMA, and D-amphetamine; 31 subjects received LSD and psilocybin; and 25 subjects received psilocybin and escitalopram. At the end-of-study visit (mean 39.8 days after last study session, SD 37.2), subjects were asked for any reoccurring drug effects since the initial substance effects had worn off. Those reporting reoccurring perception changes more than 24 h after administration were contacted for follow-up (mean follow-up duration: 31.2 months, SD 28.6).

Results: Thirteen out of 142 subjects reported reoccurring drug-like experiences (LSD: seven, psilocybin: two, both: four). The reported phenomena were predominantly mild and perceived as neutral to pleasant. Flashbacks were mostly of visual nature, lasted for seconds to minutes, and occurred within a week after the last drug administration. Two subjects reported distressing experiences that subsided spontaneously. One subject reported brief and pleasant visual perception changes which reoccurred for 7 months. None of the subjects reported impairment in their daily lives. None of the cases met DSM-V criteria for HPPD.

Conclusion: Reoccurring drug-like experiences after the administration of LSD and psilocybin are a common phenomenon occurring in up to 9.2% of healthy subjects (7.8% for LSD, 8.3% for psilocybin and 14.3% if both substances are administered). Additionally, our work suggests that flashback phenomena are not a clinically relevant problem in controlled studies with healthy participants.
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http://dx.doi.org/10.1007/s00213-022-06066-zDOI Listing
June 2022

Acute Effects of Psilocybin After Escitalopram or Placebo Pretreatment in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Subjects.

Clin Pharmacol Ther 2022 04 22;111(4):886-895. Epub 2021 Nov 22.

Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.

The psychedelic psilocybin is being investigated for the treatment of depression and anxiety. Unclear is whether antidepressant treatments interact with psilocybin. The present study used a double-blind, placebo-controlled, crossover design with two experimental test sessions to investigate the response to psilocybin (25 mg) in healthy subjects after pretreatment with escitalopram or placebo. The treatment order was random and counterbalanced. Pretreatment consisted of 10 mg escitalopram daily for 7 days, followed by 20 mg daily for 7 days, including the day of psilocybin administration, or 14 days of placebo pretreatment before psilocybin administration. Psilocybin treatments were separated by at least 16 days. The outcome measures included self-rating scales that evaluated subjective effects, autonomic effects, adverse effects, plasma brain-derived neurotrophic factor (BDNF) levels, electrocardiogram QTc time, whole-blood HTR2A and SCL6A4 gene expression, and pharmacokinetics. Escitalopram pretreatment had no relevant effect on positive mood effects of psilocybin but significantly reduced bad drug effects, anxiety, adverse cardiovascular effects, and other adverse effects of psilocybin compared with placebo pretreatment. Escitalopram did not alter the pharmacokinetics of psilocin. The half-life of psychoactive free (unconjugated) psilocin was 1.8 hours (range 1.1-2.2 hours), consistent with the short duration of action of psilocybin. Escitalopram did not alter HTR2A or SCL6A4 gene expression before psilocybin administration, QTc intervals, or circulating BDNF levels before or after psilocybin administration. Further studies are needed with a longer antidepressant pretreatment time and patients with psychiatric disorders to further define interactions between antidepressants and psilocybin.
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http://dx.doi.org/10.1002/cpt.2487DOI Listing
April 2022

Dosing Psychedelics and MDMA.

Curr Top Behav Neurosci 2021 Nov 4. Epub 2021 Nov 4.

Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.

Classic psychedelics, including psilocybin, lysergic acid diethylamide (LSD), dimethyltryptamine, and mescaline, and entactogens/empathogens, especially 3,4-methylenedioxymethamphetamine, have received renewed attention in psychiatric research and may be developed into medications for such indications as anxiety, depression, cluster headache, and posttraumatic stress disorder, among others. However, identifying proper doses is crucial. Controlled study data on dosing using well-characterized pharmaceutical formulations of the substances are scarce. The dose equivalence of different substances, dose-response effects, and subjective effects of different doses are of great interest and practically important for their clinical use in psychotherapy. Furthermore, the so-called microdosing of psychedelics has recently gained popularity, and the first placebo-controlled studies of LSD have been published. This chapter discusses different aspects of psychedelic dosing, including pharmaceutical aspects, definitions and characteristics of different doses, including microdoses, aspects of personalized dosing, and non-pharmacological factors, that can influence the response to psychedelics.
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http://dx.doi.org/10.1007/7854_2021_270DOI Listing
November 2021

Correction to: Safety pharmacology of acute LSD administration in healthy subjects.

Psychopharmacology (Berl) 2022 Feb;239(2):661

Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel and University of Basel, Schanzenstrasse 55, CH‑4056, Basel, Switzerland.

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http://dx.doi.org/10.1007/s00213-021-05988-4DOI Listing
February 2022

Safety pharmacology of acute LSD administration in healthy subjects.

Psychopharmacology (Berl) 2022 Jun 13;239(6):1893-1905. Epub 2021 Sep 13.

Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel and University of Basel, Schanzenstrasse 55, CH-4056, Basel, Switzerland.

Rationale: Lysergic acid diethylamide (LSD) is used in psychiatric and psychological research and investigated as a potential treatment for medical and psychiatric disorders, including depression, anxiety, and cluster headache.

Objectives: Safety data on clinical safety are available from small studies but not from larger samples. We report safety pharmacology data from a large pooled study sample on acute effects of LSD in healthy subjects.

Methods: We conducted a pooled analysis of four double-blind, randomized, placebo-controlled, crossover studies that included a total of 83 healthy subjects and 131 single-dose administrations of LSD. LSD administrations were matched to dose groups according to measured LSD peak plasma concentrations to adjust for uncertainties in the correct LSD dose in some studies. Single doses were 25, 50, 100, and 200 µg of LSD base. We investigated subjective effects (self-rated any drug effect, good drug effect, bad drug effect, and anxiety), blood pressure, heart rate, body temperature, duration of the acute LSD response, acute (12 h) and subacute (24 h) adverse effects, reports of flashbacks, and liver and kidney function before and after the studies.

Results: LSD dose-dependently increased subjective, physiologic, and adverse effects. The dose-response curves for the proportions of subjects with a certain amount of a subjective effect were steeper and reached a higher maximum for positive acute subjective effects compared with negative acute subjective effects. Maximal ratings of > 50% good drug effects were reached in 37%, 91%, 96%, and 91% of the LSD administrations at 25, 50, 100, and 200 µg. Maximal ratings of > 50% bad drug effects were reached in 0%, 9%, 27%, 31% at 25, 50, 100, and 200 µg, respectively. Mean ratings of Oceanic Boundlessness were 10%, 25%, 41%, and 44%, and mean ratings of Anxious Ego-Dissolution were 3.4%, 13%, 20%, and 22% at 25, 50, 100, and 200 µg, respectively. The physiologic effects of LSD were moderate. None of the subjects had systolic blood pressure > 180 mmHg at any time. Peak heart rate > 100 beats/min was observed in 0%, 6%, 20%, and 25% of the subjects at 25, 50, 100, and 200 µg, respectively. Maximal heart rates of 129 and 121 beats/min were observed in one subject at the 50 and 200 µg doses, respectively. Peak body temperature > 38° was observed in 0%, 11%, 7%, and 34% at 25, 50, 100, and 200 µg, respectively. Mean acute adverse effect scores on the List of Complaints were 5.6, 9.2, 12, and 13 at 25, 50, 100, and 200 µg, respectively. Kidney and liver function parameters were unaltered. Six subjects reported transient flashback phenomena.

Conclusions: The single-dose administration of LSD is safe in regard to acute psychological and physical harm in healthy subjects in a controlled research setting.
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http://dx.doi.org/10.1007/s00213-021-05978-6DOI Listing
June 2022

The Pharmacological Profile of Second Generation Pyrovalerone Cathinones and Related Cathinone Derivative.

Int J Mol Sci 2021 Jul 31;22(15). Epub 2021 Jul 31.

Division of Psychopharmacology Research, Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.

Pyrovalerone cathinones are potent psychoactive substances that possess a pyrrolidine moiety. Pyrovalerone-type novel psychoactive substances (NPS) are continuously detected but their pharmacology and toxicology are largely unknown. We assessed several pyrovalerone and related cathinone derivatives at the human norepinephrine (NET), dopamine (DAT), and serotonin (SERT) uptake transporters using HEK293 cells overexpressing each respective transporter. We examined the transporter-mediated monoamine efflux in preloaded cells. The receptor binding and activation potency was also assessed at the 5-HT, 5-HT, 5-HT, and 5-HT receptors. All pyrovalerone cathinones were potent DAT (IC = 0.02-8.7 μM) and NET inhibitors (IC = 0.03-4.6 μM), and exhibited no SERT activity at concentrations < 10 μM. None of the compounds induced monoamine efflux. NEH was a potent DAT/NET inhibitor (IC = 0.17-0.18 μM). 4F-PBP and NEH exhibited a high selectivity for the DAT (DAT/SERT ratio = 264-356). Extension of the alkyl chain enhanced NET and DAT inhibition potency, while presence of a 3,4-methylenedioxy moiety increased SERT inhibition potency. Most compounds did not exhibit any relevant activity at other monoamine receptors. In conclusion, 4F-PBP and NEH were selective DAT/NET inhibitors indicating that these substances likely produce strong psychostimulant effects and have a high abuse liability.
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http://dx.doi.org/10.3390/ijms22158277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348686PMC
July 2021

Role of the 5-HT Receptor in Acute Effects of LSD on Empathy and Circulating Oxytocin.

Front Pharmacol 2021 13;12:711255. Epub 2021 Jul 13.

Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.

The psychedelic lysergic acid diethylamide (LSD) has experienced a revival in research, including clinical trials that evaluate LSD-assisted psychotherapy. LSD induces perceptual alterations and influences emotion processing in ways that may support psychotherapy. Here, we investigated the effects of LSD on emotional empathy and mediating role of the serotonin 5-hydroxytryptamine-2A (5-HT) receptor by administering 25, 50, 100, and 200 µg LSD alone and 200 µg LSD combined with pretreatment with the 5-HT receptor antagonist ketanserin (40 mg) using a placebo-controlled, double-blind, random-order, crossover design in 16 healthy subjects. The Multifaceted Empathy Test (MET) was used to assess the effects of LSD on emotional empathy. Plasma oxytocin levels were also measured. LSD dose-dependently increased implicit and explicit emotional empathy, with the highest 200 µg LSD dose having a significant effect compared with placebo. The 200 µg dose of LSD also moderately increased plasma oxytocin levels compared with placebo. Ketanserin reduced the LSD-induced elevations of oxytocin but not the LSD-induced increases in emotional empathy. These findings confirm that LSD enhances empathy, and this effect may be partially independent of its primary action on 5-HT receptors to induce subjective psychedelic effects. In contrast, LSD-induced oxytocin release may depend on 5-HT receptor stimulation, which is consistent with the psychedelic effect of LSD. Further studies are needed to investigate whether LSD may also enhance empathy and potentially produce therapeutic effects in patients who have deficits in empathy and impairments in social functioning.
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http://dx.doi.org/10.3389/fphar.2021.711255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313809PMC
July 2021

Molecular and clinical aspects of potential neurotoxicity induced by new psychoactive stimulants and psychedelics.

Exp Neurol 2021 09 4;343:113778. Epub 2021 Jun 4.

Division of Clinical Pharmacology and Toxicology, University Hospital Basel and University of Basel, Basel, Switzerland; Institute of Pharmacology, Medical University of Vienna, Vienna, Austria; Institute of Applied Physics, TU Wien, Vienna, Austria. Electronic address:

New psychoactive stimulants and psychedelics continue to play an important role on the illicit new psychoactive substance (NPS) market. Designer stimulants and psychedelics both affect monoaminergic systems, although by different mechanisms. Stimulant NPS primarily interact with monoamine transporters, either as inhibitors or as substrates. Psychedelic NPS most potently interact with serotonergic receptors and mediate their mind-altering effects mainly through agonism at serotonin 5-hydroxytryptamine-2A (5-HT) receptors. Rarely, designer stimulants and psychedelics are associated with potentially severe adverse effects. However, due to the high number of emerging NPS, it is not possible to investigate the toxicity of each individual substance in detail. The brain is an organ particularly sensitive to substance-induced toxicity due to its high metabolic activity. In fact, stimulant and psychedelic NPS have been linked to neurological and cognitive impairments. Furthermore, studies using in vitro cell models or rodents indicate a variety of mechanisms that could potentially lead to neurotoxic damage in NPS users. Cytotoxicity, mitochondrial dysfunction, and oxidative stress may potentially contribute to neurotoxicity of stimulant NPS in addition to altered neurochemistry. Serotonin 5-HT receptor-mediated toxicity, oxidative stress, and activation of mitochondrial apoptosis pathways could contribute to neurotoxicity of some psychedelic NPS. However, it remains unclear how well the current preclinical data of NPS-induced neurotoxicity translate to humans.
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http://dx.doi.org/10.1016/j.expneurol.2021.113778DOI Listing
September 2021

Genetic influence of CYP2D6 on pharmacokinetics and acute subjective effects of LSD in a pooled analysis.

Sci Rep 2021 05 25;11(1):10851. Epub 2021 May 25.

Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, Schanzenstrasse 55, 4056, Basel, Switzerland.

Lysergic acid diethylamide (LSD) is a classic psychedelic substance that is used recreationally and investigated in psychiatric research. There are no pharmacogenetic studies on LSD. In vitro metabolic studies indicate that several cytochrome P450 (CYP) isoforms (e.g., CYP2D6, CYP1A2, and CYP2C9) are involved in LSD metabolism, but in vivo data are scarce. The present study examined the influence of genetic polymorphisms of CYP genes on the pharmacokinetics and acute effects of LSD in healthy subjects. We identified common genetic variants of CYPs (CYP2D6, CYP1A2, CYP2C9, CYP2C19, and CYP2B6) in 81 healthy subjects who were pooled from four randomized, placebo-controlled, double-blind Phase 1 studies. We found that genetically determined CYP2D6 functionality significantly influenced the pharmacokinetics of LSD. Individuals with no functional CYP2D6 (i.e., poor metabolizers) had longer LSD half-lives and approximately 75% higher parent drug and main metabolite 2-oxo-3-hydroxy LSD area-under-the-curve blood plasma concentrations compared with carriers of functional CYP2D6. Non-functional CYP2D6 metabolizers also exhibited greater alterations of mind and longer subjective effect durations in response to LSD compared with functional CYP2D6 metabolizers. No effect on the pharmacokinetics or acute effects of LSD were observed with other CYPs. These findings indicate that genetic polymorphisms of CYP2D6 significantly influence the pharmacokinetic and subjective effects of LSD. Given the potential therapeutic use of psychedelics, including LSD, the role of pharmacogenetic tests prior to LSD-assisted psychotherapy needs to be further investigated.
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http://dx.doi.org/10.1038/s41598-021-90343-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149637PMC
May 2021

Low Doses of LSD Acutely Increase BDNF Blood Plasma Levels in Healthy Volunteers.

ACS Pharmacol Transl Sci 2021 Apr 31;4(2):461-466. Epub 2020 Aug 31.

Department of Neuropsychology & Psychopharmacology, Faculty of Psychology & Neuroscience, Maastricht University, Maastricht 6200 MD, The Netherlands.

Despite preclinical evidence for psychedelic-induced neuroplasticity, confirmation in humans is grossly lacking. Given the increased interest in using low doses of psychedelics for psychiatric indications and the importance of neuroplasticity in the therapeutic response, this placebo-controlled within-subject study investigated the effect of single low doses of LSD (5, 10, and 20 μg) on circulating BDNF levels in healthy volunteers. Blood samples were collected every 2 h over 6 h, and BDNF levels were determined afterward in blood plasma using ELISA. The findings demonstrated an increase in BDNF blood plasma levels at 4 h (5 μg) and 6 h (5 and 20 μg) compared to that for the placebo. The finding that LSD acutely increases BDNF levels warrants studies in patient populations.
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http://dx.doi.org/10.1021/acsptsci.0c00099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033605PMC
April 2021

Acute subjective effects in LSD- and MDMA-assisted psychotherapy.

J Psychopharmacol 2021 04 8;35(4):362-374. Epub 2020 Oct 8.

Department of Biomedicine, University Hospital Basel, Basel, Switzerland.

Background: Lysergic acid diethylamide (LSD) and 3,4-methylenedioxymethamphetamine (MDMA) were used in psychotherapy in the 1960s-1980s, and are currently being re-investigated as treatments for several psychiatric disorders. In Switzerland, limited medical use of these substances is possible in patients not responding to other treatments (compassionate use).

Methods: This study aimed to describe patient characteristics, treatment indications and acute alterations of mind in patients receiving LSD (100-200 µg) and/or MDMA (100-175 mg) within the Swiss compassionate use programme from 2014-2018. Acute effects were assessed using the 5 Dimensions of Altered States of Consciousness scale and the Mystical Experience Questionnaire, and compared with those in healthy volunteers administered with LSD or MDMA and patients treated alone with LSD in clinical trials.

Results: Eighteen patients (including 12 women and six men, aged 29-77 years) were treated in group settings. Indications mostly included posttraumatic stress disorder and major depression. Generally, a drug-assisted session was conducted every 3.5 months after 3-10 psychotherapy sessions. LSD induced pronounced alterations of consciousness on the 5 Dimensions of Altered States of Consciousness scale, and mystical-type experiences with increases in all scales on the Mystical Experience Questionnaire. Effects were largely comparable between patients in the compassionate use programme and patients or healthy subjects treated alone in a research setting.

Conclusion: LSD and MDMA are currently used medically in Switzerland mainly in patients with posttraumatic stress disorder and depression in group settings, producing similar acute responses as in research subjects. The data may serve as a basis for further controlled studies of substance-assisted psychotherapy.
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http://dx.doi.org/10.1177/0269881120959604DOI Listing
April 2021

Prediction of MDMA response in healthy humans: a pooled analysis of placebo-controlled studies.

J Psychopharmacol 2021 05 30;35(5):556-565. Epub 2021 Mar 30.

Division of Clinical Pharmacology and Toxicology, University Hospital Basel, Basel, Switzerland.

Background: 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is used both recreationally and therapeutically. Little is known about the factors influencing inter- and intra-individual differences in the acute response to MDMA. Effects of other psychoactive substances have been shown to be critically influenced by personality traits and mood state before intake.

Methods: We pooled data from 10 randomized, double-blind, placebo-controlled, cross-over studies performed in the same laboratory in 194 healthy subjects receiving doses of 75 or 125mg of MDMA. We investigated the influence of drug dose, body weight, sex, age, drug pre-experience, genetics, personality and mental state before drug intake on the acute physiological and psychological response to MDMA.

Results: In univariable analyses, the MDMA plasma concentration was the strongest predictor for most outcome variables. When adjusting for dose per body weight, we found that (a) a higher activity of the enzyme CYP2D6 predicted lower MDMA plasma concentration, (b) a higher score in the personality trait "openness to experience" predicted more perceived "closeness", a stronger decrease in "general inactivation", and higher scores in the 5D-ASC (5 Dimensions of Altered States of Consciousness Questionnaire) scales "oceanic boundlessness" and "visionary restructuralization", and (c) subjects with high "neuroticism" or trait anxiety were more likely to have unpleasant and/or anxious reactions.

Conclusions: Although MDMA plasma concentration was the strongest predictor, several personality traits and mood state variables additionally explained variance in the response to MDMA. The results confirm that both pharmacological and non-pharmacological variables influence the response to MDMA. These findings may be relevant for the therapeutic use of MDMA.
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http://dx.doi.org/10.1177/0269881121998322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155734PMC
May 2021

Variation of drugs involved in acute drug toxicity presentations based on age and sex: an epidemiological approach based on European emergency departments.

Clin Toxicol (Phila) 2021 Oct 16;59(10):896-904. Epub 2021 Mar 16.

Emergency Department, Hospital Clínic, IDIBAPS, Barcelona, Spain.

Objective: To analyse the relative percentage of acute recreational drug toxicity emergency department (ED) presentations involving the main drug groups according to age and sex and investigate different patterns based on sex and age strata.

Methods: We analysed all patients with acute recreational drug toxicity included by the Euro-DEN Plus dataset (22 EDs in 14 European countries) between October 2013 and December 2016 (39 months). Drugs were grouped as: opioids, cocaine, cannabis, amphetamines, gamma-hydroxybutyrate (GHB), hallucinogens, new psychoactive substances (NPS), benzodiazepines and ketamine. Descriptive data by age and sex are presented and compared among age/sex categories and among drug families.

Results: Of 17,371 patients were included during the 39-month period, 17,198 (99.0%) had taken at least one of the investigated drugs (median age: 31 years; 23.9% female; ethanol co-ingestion recorded in 41.5%, unknown in 31.2%; multiple drug use in 37.9%). Opioids (in 31.4% of patients) and amphetamines (23.3%) were the most frequently involved and hallucinogens (1.9%) and ketamine (1.7%) the least. Overall, female patients were younger than males, both in the whole cohort (median age 29 vs. 32 years;  < 0.001) and in all drug groups except benzodiazepines (median age 36 vs. 36 years;  = 0.83). The relative proportion of each drug group was different at every age strata and some patterns could be clearly described: cannabis, NPS and hallucinogens were the most common in patients <20 years; amphetamines, ketamine and cocaine in the 20- to 39-year group; GHB/GBL in the 30- to 39-year group; and opioids and benzodiazepines in patients ≥40 years. Ethanol and other drug co-ingestion was more frequent at middle-ages, and multidrug co-ingestion was more common in females than males.

Conclusion: Differences in the drugs involved in acute drug toxicity presentations according to age and sex may be relevant for developing drug-prevention and education programs for some particular subgroups of the population based on the increased risk of adverse events in specific sex and/or age strata.
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http://dx.doi.org/10.1080/15563650.2021.1884693DOI Listing
October 2021

Development and validation of an LC-MS/MS method for the bioanalysis of psilocybin's main metabolites, psilocin and 4-hydroxyindole-3-acetic acid, in human plasma.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Feb 7;1164:122486. Epub 2020 Dec 7.

Division of Clinical Pharmacology and Toxicology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland; Division of Clinical Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland. Electronic address:

Psilocin is the active metabolite of psilocybin, a serotonergic psychedelic substance. It is used recreationally and investigated in substance-assisted psychotherapy. The pharmacokinetic properties of psilocin are only partially characterized. Therefore, we developed and validated a rapid LC-MS/MS method to quantify psilocin and its metabolite 4-hydroxyindole-3-acetic acid (4-HIAA) in human plasma. Plasma samples were processed by protein precipitation using methanol. The injected sample was mixed with water in front of a C analytical column to increase retention of the analytes. Psilocin and 4-HIAA were detected by multiple reaction monitoring (MRM) in positive and negative electrospray ionisation mode, respectively. An inter-assay accuracy of 100-109% and precision of ≤8.7% was recorded over three validation runs. The recovery was near to complete (≥94.7%) and importantly, consistent over different concentration levels and plasma batches (CV%: ≤4.1%). The plasma matrix caused negligible ion suppression and endogenous interferences could be separated from the analytes. Psilocin and 4-HIAA plasma samples could be thawed and re-frozen for three cycles, kept at room temperature for 8 h or 1 month at -20 °C without showing degradation (≤10%). The linear range (R ≥ 0.998) of the method covered plasma concentrations observed in humans following a common therapeutic oral dose of 25 mg psilocybin and was therefore able to assess the pharmacokinetics of psilocin and 4-HIAA. The LC-MS/MS method was convenient and reliable for measuring psilocin and 4-HIAA in plasma and will facilitate the clinical development of psilocybin.
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http://dx.doi.org/10.1016/j.jchromb.2020.122486DOI Listing
February 2021

MDMA-induced changes in within-network connectivity contradict the specificity of these alterations for the effects of serotonergic hallucinogens.

Neuropsychopharmacology 2021 02 20;46(3):545-553. Epub 2020 Nov 20.

Department of Psychiatry (UPK), University of Basel, Basel, 4002, Switzerland.

It has been reported that serotonergic hallucinogens like lysergic acid diethylamide (LSD) induce decreases in functional connectivity within various resting-state networks. These alterations were seen as reflecting specific neuronal effects of hallucinogens and it was speculated that these shifts in connectivity underlie the characteristic subjective drug effects. In this study, we test the hypothesis that these alterations are not specific for hallucinogens but that they can be induced by monoaminergic stimulation using the non-hallucinogenic serotonin-norepinephrine-dopamine releasing agent 3,4-methylenedioxymethamphetamine (MDMA). In a randomized, placebo-controlled, double-blind, crossover design, 45 healthy participants underwent functional magnetic resonance imaging (fMRI) following oral administration of 125 mg MDMA. The networks under question were identified using independent component analysis (ICA) and were tested with regard to within-network connectivity. Results revealed decreased connectivity within two visual networks, the default mode network (DMN), and the sensorimotor network. These findings were almost identical to the results previously reported for hallucinogenic drugs. Therefore, our results suggest that monoaminergic substances can induce widespread changes in within-network connectivity in the absence of marked subjective drug effects. This contradicts the notion that these alterations can be regarded as specific for serotonergic hallucinogens. However, changes within the DMN might explain antidepressants effects of some of these substances.
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http://dx.doi.org/10.1038/s41386-020-00906-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027447PMC
February 2021

Treatment of a Complex Personality Disorder Using Repeated Doses of LSD-A Case Report on Significant Improvements in the Absence of Acute Drug Effects.

Front Psychiatry 2020 22;11:573953. Epub 2020 Oct 22.

University of Basel, Department of Psychiatry (Universitäre Psychiatrische Kliniken), Basel, Switzerland.

A 39-year-old female patient suffering from severe, treatment-resistant depression and other symptoms associated with a complex personality disorder was admitted to our open psychiatric ward for an experimental treatment with lysergic acid diethylamide (LSD). The substance was administered in repeated weekly and ascending doses. Curiously, there were no substantial acute subjective effects of the drug despite adequate dosing, which was also confirmed by plasma drug concentration monitoring. However, the patient showed rapid and significant improvement with most notable changes in depressed mood, emotional instability, loss of energy, and suicidal ideations. Additionally, the SCL-90 questionnaire indicated significant decreases in global severity and in various psychopathological subscales. Improvements persisted for ~7 days after each administration. Due to the severe course of the illness and the resistance to previous treatment it was decided to continue this experimental approach with weekly repeated doses of LSD. The patient will be observed closely with regard to somatic and mental side effects. Two features of this case are remarkable: Firstly, administration of LSD was associated with significant improvements in various symptoms of a condition usually difficult to treat. Secondly, symptom reductions occurred in the absence of acute drug effects. Therefore, the mechanism of action seemed to deviate from the concept that improvements after administration of drugs like LSD are due to experiences during the acute drug effects. This case might indicate that LSD can induce rapid but transient beneficial effects on several psychopathological symptoms. The time course of these improvements resembled antidepressant effects seen after administration of ketamine.
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http://dx.doi.org/10.3389/fpsyt.2020.573953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643748PMC
October 2020

Mood and cognition after administration of low LSD doses in healthy volunteers: A placebo controlled dose-effect finding study.

Eur Neuropsychopharmacol 2020 12 17;41:81-91. Epub 2020 Oct 17.

Department of Neuropsychology & Psychopharmacology, Faculty of Psychology & Neuroscience, Maastricht University, Maastricht, the Netherlands.

There is a popular interest in microdosing with psychedelics such as LSD. This practice of using one-tenth of a full psychedelic dose according to a specific dosing schedule, anecdotally enhances mood and performance. Nonetheless, controlled research on the efficacy of microdosing is scarce. The main objective of the present dose-finding study was to determine the minimal dose of LSD needed to affect mood and cognition. A placebo-controlled within-subject study including 24 healthy participants, was conducted to assess the acute effects of three LSD doses (5, 10, and 20 mcg) on measures of cognition, mood, and subjective experience, up until 6 h after administration. Cognition and subjective experience were assessed using the Psychomotor Vigilance Task, Digit Symbol Substitution Test, Cognitive Control Task, Profile of Mood States, and 5-Dimensional Altered States of Consciousness rating scale. LSD showed positive effects in the majority of observations by increasing positive mood (20 mcg), friendliness (5, 20 mcg), arousal (5 mcg), and decreasing attentional lapses (5, 20 mcg). Negative effects manifested as an increase in confusion (20 mcg) and anxiety (5, 20 mcg). Psychedelic-induced changes in waking consciousness were also present (10, 20 mcg). Overall, the present study demonstrated selective, beneficial effects of low doses of LSD on mood and cognition in the majority of observations. The minimal LSD dose at which subjective and performance effects are notable is 5 mcg and the most apparent effects were visible after 20 mcg.
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http://dx.doi.org/10.1016/j.euroneuro.2020.10.002DOI Listing
December 2020

Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects.

Neuropsychopharmacology 2021 02 15;46(3):537-544. Epub 2020 Oct 15.

Department of Biomedicine and Department of Clinical Research, Clinical Pharmacology and Toxicology, University Hospital Basel, Basel, Switzerland.

Growing interest has been seen in using lysergic acid diethylamide (LSD) in psychiatric research and therapy. However, no modern studies have evaluated subjective and autonomic effects of different and pharmaceutically well-defined doses of LSD. We used a double-blind, randomized, placebo-controlled, crossover design in 16 healthy subjects (eight women, eight men) who underwent six 25 h sessions and received placebo, LSD (25, 50, 100, and 200 µg), and 200 µg LSD 1 h after administration of the serotonin 5-hydroxytryptamine-2A (5-HT) receptor antagonist ketanserin (40 mg). Test days were separated by at least 10 days. Outcome measures included self-rating scales that evaluated subjective effects, autonomic effects, adverse effects, plasma brain-derived neurotrophic factor levels, and pharmacokinetics up to 24 h. The pharmacokinetic-subjective response relationship was evaluated. LSD showed dose-proportional pharmacokinetics and first-order elimination and dose-dependently induced subjective responses starting at the 25 µg dose. A ceiling effect was observed for good drug effects at 100 µg. The 200 µg dose of LSD induced greater ego dissolution than the 100 µg dose and induced significant anxiety. The average duration of subjective effects increased from 6.7 to 11 h with increasing doses of 25-200 µg. LSD moderately increased blood pressure and heart rate. Ketanserin effectively prevented the response to 200 µg LSD. The LSD dose-response curve showed a ceiling effect for subjective good effects, and ego dissolution and anxiety increased further at a dose above 100 µg. These results may assist with dose finding for future LSD research. The full psychedelic effects of LSD are primarily mediated by serotonin 5-HT receptor activation.
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http://dx.doi.org/10.1038/s41386-020-00883-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027607PMC
February 2021

Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide Microdoses in Healthy Participants.

Clin Pharmacol Ther 2021 03 18;109(3):658-666. Epub 2020 Oct 18.

Department of Neuropsychology & Psychopharmacology, Faculty of Psychology & Neuroscience, Maastricht University, Maastricht, The Netherlands.

"Microdoses" of lysergic acid diethylamide (LSD) are used recreationally to enhance mood and cognition. Increasing interest has also been seen in developing LSD into a medication. Therefore, we performed a pharmacokinetic-pharmacodynamic study using very low doses of LSD. Single doses of LSD base (5, 10, and 20 µg) and placebo were administered in a double-blind, randomized, placebo-controlled crossover study in 23 healthy participants. Test days were separated by at least 5 days. Plasma levels of LSD and subjective effects were assessed up to 6 hours after administration. Pharmacokinetic parameters were determined using compartmental modeling. Concentration-subjective effect relationships were described using pharmacokinetic-pharmacodynamic modeling. Mean (95% confidence interval) maximal LSD concentrations were 151 pg/mL (127-181), 279 pg/mL (243-320), and 500 pg/mL (413-607) after 5, 10, and 20 µg LSD administration, respectively. Maximal concentrations were reached after 1.1 hours. The mean elimination half-life was 2.7 hours (1.5-6.2). The 5 µg dose of LSD elicited no significant acute subjective effects. The 10 µg dose of LSD significantly increased ratings of "under the influence" and "good drug effect" compared with placebo. These effects began an average of 1.1 hours after 10 µg LSD administration, peaked at 2.5 hours, and ended at 5.1 hours. The 20 µg dose of LSD significantly increased ratings of "under the influence," "good drug effects," and "bad drug effects." LSD concentrations dose-proportionally increased at doses as low as 5-20 µg and decreased with a half-life of 3 hours. The threshold dose of LSD base for psychotropic effects was 10 µg.
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http://dx.doi.org/10.1002/cpt.2057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984326PMC
March 2021

A low dose of lysergic acid diethylamide decreases pain perception in healthy volunteers.

J Psychopharmacol 2021 04 25;35(4):398-405. Epub 2020 Aug 25.

Department of Neuropsychology & Psychopharmacology, Faculty of Psychology & Neuroscience, Maastricht University, Maastricht, the Netherlands.

Background: Lysergic acid diethylamide (LSD) is an ergot alkaloid derivative with psychedelic properties that has been implicated in the management of persistent pain. Clinical studies in the 1960s and 1970s have demonstrated profound analgesic effects of full doses of LSD in terminally ill patients, but this line of research evaporated after LSD was scheduled worldwide.

Aim: The present clinical study is the first to revisit the potential of LSD as an analgesic, and at dose levels which are not expected to produce profound mind-altering effects.

Methods: Twenty-four healthy volunteers received single doses of 5, 10 and 20 µg LSD as well as placebo on separate occasions. A Cold Pressor Test was administered at 1.5 and 5 h after treatment administration to assess pain tolerance to experimentally evoked pain. Ratings of dissociation and psychiatric symptoms as well as assessments of vital signs were included to monitor mental status as well as safety during treatments.

Results: LSD 20 µg significantly increased the time that participants were able to tolerate exposure to cold (3°C) water and decreased their subjective levels of experienced pain and unpleasantness. LSD elevated mean blood pressure within the normal range and slightly increased ratings of dissociation, anxiety and somatization.

Conclusion: The present study provides evidence of a protracted analgesic effect of LSD at a dose that is low enough to avoid a psychedelic experience. The present data warrant further research into the analgesic effects of low doses of LSD in patient populations.
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http://dx.doi.org/10.1177/0269881120940937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054163PMC
April 2021

Comparative Untargeted Metabolomics Analysis of the Psychostimulants 3,4-Methylenedioxy-Methamphetamine (MDMA), Amphetamine, and the Novel Psychoactive Substance Mephedrone after Controlled Drug Administration to Humans.

Metabolites 2020 Jul 27;10(8). Epub 2020 Jul 27.

Department of Forensic Pharmacology & Toxicology, Zurich Institute of Forensic Medicine, University of Zurich, 8057 Zurich, Switzerland.

Psychoactive stimulants are a popular drug class which are used recreationally. Over the last decade, large numbers of new psychoactive substances (NPS) have entered the drug market and these pose a worldwide problem to human health. Metabolomics approaches are useful tools for simultaneous detection of endogenous metabolites affected by drug use. They allow identification of pathways or characteristic metabolites, which might support the understanding of pharmacological actions or act as indirect biomarkers of consumption behavior or analytical detectability. Herein, we performed a comparative metabolic profiling of three psychoactive stimulant drugs 3,4-methylenedioxymethamphetamine (MDMA), amphetamine and the NPS mephedrone by liquid chromatography-high resolution mass spectrometry (LC-HRMS) in order to identify common pathways or compounds. Plasma samples were obtained from controlled administration studies to humans. Various metabolites were identified as increased or decreased based on drug intake, mainly belonging to energy metabolism, steroid biosynthesis and amino acids. Linoleic acid and pregnenolone-sulfate changed similarly in response to intake of all drugs. Overall, mephedrone produced a profile more similar to that of amphetamine than MDMA in terms of affected energy metabolism. These data can provide the basis for further in-depth targeted metabolome studies on pharmacological actions and search for biomarkers of drug use.
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http://dx.doi.org/10.3390/metabo10080306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465486PMC
July 2020

MDMA-related presentations to the emergency departments of the European Drug Emergencies Network plus (Euro-DEN Plus) over the four-year period 2014-2017.

Clin Toxicol (Phila) 2021 Feb 17;59(2):131-137. Epub 2020 Jul 17.

Division of Clinical Pharmacology and Toxicology, Institute of Pharmacological Sciences of Southern Switzerland, Ente Ospedaliero Cantonale, Lugano, Switzerland.

Context: 3,4-Methylenedioxymethamphetamine (MDMA) remains one of the most commonly used recreational drugs in Europe. Monitoring of Emergency Department (ED) presentations with acute toxicity associated with MDMA is important to determine trends in MDMA use and harms.

Methods: Data were extracted from the European Drug Emergencies Network (Euro-DEN) Plus database for all ED presentations with acute toxicity involving MDMA use, alone or in combination with other substances, between 1 January 2014 and 31 December 2017. Geographical distribution, time trends, patient demographics, clinical features, management and outcome were analysed.

Results: Out of 23,947 presentations, 2013 (8.4%) involved MDMA, used alone (88, 4.4%) or with other substances (1925, 95.6%). The proportion of MDMA presentations varied by country, from over 15% in France to less than 5% in Norway. For the 15 sentinel centres where data were available for all four years, MDMA-related presentations peaked in 2016 (10.4% 8.1% in 2015,  < 0.0001), thereafter decreasing in 2017 (8.2%,  = 0.0002). 1436 (71.3%) presentations involved males. Females were significantly younger than males (median 23 years, interquartile range, IQR, 20-27 years, median 25 years, IQR 21-30 years,  < 0.0001). Compared to presentations of acute toxicity with lone-use cocaine, presentations with lone-use MDMA occurred more frequently during the weekend (58.0% 43.9%,  = 0.02), were more frequently medically discharged directly from the ED (74.7% 62.4%,  = 0.03), and less frequently received sedation (43.5% 66.5%,  = 0.003).

Conclusions: This large multicentre series of MDMA presentations to EDs showed geographical variation and changes in time trends and in patient demographics. Triangulation with data from complementary sources including seizures, prevalence of use and wastewater analysis, will enable a greater understanding of the public health implications of MDMA use in Europe.
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http://dx.doi.org/10.1080/15563650.2020.1784914DOI Listing
February 2021
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