48 results on '"Holze F"'
Search Results
2. Acute effects of MDMA and LSD co-administration in healthy participants
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Straumann, I., primary, Ley, L., additional, Holze, F., additional, Becker, A.M., additional, Klaiber, A., additional, Duthaler, U., additional, Varghese, N., additional, Eckert, A., additional, and Liechti, M.E., additional
- Published
- 2023
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3. Acute effects of intravenous DMT in a randomized placebo-controlled study in healthy participants
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Vogt, S., primary, Ley, L., additional, Erne, L., additional, Straumann, I., additional, Becker, A.M., additional, Klaiber, A., additional, Holze, F., additional, Vandersmisssen, A., additional, Mueller, L., additional, Duthaler, U., additional, Rudin, D., additional, Luethi, D., additional, Varghese, N., additional, Eckert, A., additional, and Liechti, M.E., additional
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- 2023
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4. Ketanserin reverses the acute effects of LSD in healthy subjects
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Becker, A., Klaiber, A., Holze, F., Istampoulouoglou, I., Duthaler, U., and Liechti, M.E.
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- 2022
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5. Pharmacokinetics and pharmacokinetic-pharmacodynamic relationship of oral psilocybin administration in healthy subjects
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Holze, F., Becker, A.M., Kolaczynska, K.E., Duthaler, U., and Liechti, M.E.
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- 2022
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6. Comparison of subjective, autonomic, and endocrine effects of LSD and psilocybin in healthy subjects
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Holze, F., Ley, L., Müller, F., Nimmy, V., Eckert, A., and Liechti, M.E.
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- 2022
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7. P824. Creative Processes Under the Influence of a Low Dose of LSD: A Placebo-Controlled, Double-Blind Trial in Healthy Volunteers
- Author
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Kuypers, K., Hutten, N., Mason, N., Dolder, P., Theunissen, E., Holze, F., Liechti, M., Feilding, A., Ramaekers, J., RS: FPN NPPP II, and Section Psychopharmacology
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Creativity ,Placebo-Controlled Trial ,LSD Microdosing - Published
- 2021
8. Acute emotional and social cognitive effects of beer
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Dolder, P., primary, Holze, F., additional, Harder, S., additional, and Liechti, M., additional
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- 2016
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9. P.6.b.008 - Acute emotional and social cognitive effects of beer
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Dolder, P., Holze, F., Harder, S., and Liechti, M.
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- 2016
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10. Ketanserin exhibits dose- and concentration-proportional serotonin 2A receptor occupancy in healthy individuals: Relevance for psychedelic research.
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Holze F, Madsen MK, Svarer C, Gillings N, Stenbaek DS, Rudin D, Duthaler U, Liechti ME, Fisher PM, and Knudsen GM
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- Humans, Male, Adult, Female, Young Adult, Brain metabolism, Brain drug effects, Brain diagnostic imaging, Healthy Volunteers, Benzylamines pharmacokinetics, Benzylamines administration & dosage, Benzylamines pharmacology, Serotonin 5-HT2 Receptor Antagonists administration & dosage, Serotonin 5-HT2 Receptor Antagonists pharmacokinetics, Serotonin 5-HT2 Receptor Antagonists pharmacology, Phenethylamines pharmacokinetics, Phenethylamines administration & dosage, Ketanserin pharmacokinetics, Ketanserin administration & dosage, Receptor, Serotonin, 5-HT2A metabolism, Receptor, Serotonin, 5-HT2A drug effects, Positron-Emission Tomography, Dose-Response Relationship, Drug, Hallucinogens administration & dosage, Hallucinogens pharmacokinetics, Hallucinogens pharmacology, Hallucinogens blood
- Abstract
The serotonin 2A (5-HT2A) receptor is an important target for drug development and the main receptor through which classical psychedelics elucidate their hallucinogenic effects. The 5-HT2A receptor antagonist ketanserin has frequently been used as a tool to block the receptor. Here, we establish the dose-occupancy relation of ketanserin and the cerebral 5-HT2A receptor in healthy participants by conducting a positron emission tomography (PET) study. 120-min PET scans using the 5-HT2A receptor agonist radiotracer [
11 C]Cimbi-36 were conducted at baseline and after oral doses of either 10, 20, or 40 mg of ketanserin; each participant underwent one or two scans after ketanserin administration. Occupancy was defined as the percent change in neocortex binding potential (BPND ), estimated using the simplified reference tissue model (SRTM) with the cerebellum as reference region. Peroral ketanserin intake resulted in a plasma concentration-related increase in cerebral 5-HT2A receptor occupancy with the highest plasma ketanserin concentrations measured after ∼2 h. The relation between mean plasma ketanserin concentrations and 5-HT2A receptor occupancy conformed to a single-site binding model with an estimated EC50 (95 % CI) of 2.52 (0.75; 8.1) ng/mL, which corresponds to a peroral dose of ketanserin of approximately 10 mg. These data elucidate for the first time in humans the cerebral pharmacodynamics of ketanserin, both benefitting its use as a pharmacological tool for probing brain function and adding to its potential for therapeutic use in rescuing a bad psychedelic experience., Competing Interests: Declaration of competing interest MKM has received an honorarium as a speaker for Lundbeck Pharma and the Lundbeck Foundation. DSS has received an honorarium as a speaker for the Lundbeck Foundation. MEL is a consultant for Mind Medicine, Inc. GMK has received honoraria as a speaker for Compass Ltd. and H. Lundbeck and is a consultant for Onsero, Pangea, and Gilgamesh, PureTechHealth, and is a board member of Elsass Foundation. All other authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)- Published
- 2024
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11. Naturalistic psychedelic therapy: The role of relaxation and subjective drug effects in antidepressant response.
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Calder AE, Rausch B, Liechti ME, Holze F, and Hasler G
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- Humans, Male, Female, Adult, Double-Blind Method, Middle Aged, Antidepressive Agents pharmacology, Antidepressive Agents administration & dosage, Depression drug therapy, Switzerland, Mysticism psychology, Relaxation, Young Adult, Psychiatric Status Rating Scales, Treatment Outcome, Hallucinogens pharmacology, Hallucinogens administration & dosage, Psilocybin pharmacology, Psilocybin administration & dosage, Lysergic Acid Diethylamide pharmacology, Lysergic Acid Diethylamide administration & dosage, Cross-Over Studies
- Abstract
Background: Psychedelic-assisted therapy (PAT) is permitted in Switzerland under its limited medical use program. Data from patients in this program represent a unique opportunity to analyze the real-world practice of PAT., Aims: This study compared the subjective effects of lysergic acid diethylamide (LSD) and psilocybin between patients undergoing PAT and healthy volunteers. For the patients, it also investigated the relationship between antidepressant effects and six measures of acute drug effects., Methods: We compared data on acute psychedelic drug effects between 28 PAT patients with data from 28 healthy participants who participated in a randomized, double-blind crossover trial. All participants received varying doses of psilocybin and LSD. Subjective effects were assessed on an hourly basis during the acute drug effects, and the Mystical Experience Questionnaire (MEQ) was completed retrospectively. For patients, depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS)., Results: Ratings of overall drug effect and mystical experience were similar across groups. Compared with healthy controls, patients reported lower ratings of ego dissolution. Patients showed a significant decrease in MADRS scores, and the greatest predictor of antidepressant outcome was relaxation during the PAT session. We did not observe a relationship between mystical-type experiences and antidepressant effects. Most patients experienced mild adverse effects which resolved within 48 h., Conclusion: PAT reduced depressive symptoms in this heterogeneous patient group. Patients may experience more challenging psychedelic effects and reduced ego dissolution. Hourly assessment of drug effects may predict clinical outcomes better than retrospectively assessed mystical experiences, and the impact of relaxation during PAT should be investigated further., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MEL is a consultant to Mind Medicine Inc. GH is a consultant to Gilgamesh Pharmaceuticals Inc. The other authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
- Published
- 2024
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12. Large-scale brain connectivity changes following the administration of lysergic acid diethylamide, d-amphetamine, and 3,4-methylenedioxyamphetamine.
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Avram M, Fortea L, Wollner L, Coenen R, Korda A, Rogg H, Holze F, Vizeli P, Ley L, Radua J, Müller F, Liechti ME, and Borgwardt S
- Abstract
Psychedelics have recently attracted significant attention for their potential to mitigate symptoms associated with various psychiatric disorders. However, the precise neurobiological mechanisms responsible for these effects remain incompletely understood. A valuable approach to gaining insights into the specific mechanisms of action involves comparing psychedelics with substances that have partially overlapping neurophysiological effects, i.e., modulating the same neurotransmitter systems. Imaging data were obtained from the clinical trial NCT03019822, which explored the acute effects of lysergic acid diethylamide (LSD), d-amphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) in 28 healthy volunteers. The clinical trial employed a double-blind, placebo-controlled, crossover design. Herein, various resting-state connectivity measures were examined, including within-network connectivity (integrity), between-network connectivity (segregation), seed-based connectivity of resting-state networks, and global connectivity. Differences between placebo and the active conditions were assessed using repeated-measures ANOVA, followed by post-hoc pairwise t-tests. Changes in voxel-wise seed-based connectivity were correlated with serotonin 2 A receptor density maps. Compared to placebo, all substances reduced integrity in several networks, indicating both common and unique effects. While LSD uniquely reduced integrity in the default-mode network (DMN), the amphetamines, in contrast to our expectations, reduced integrity in more networks than LSD. However, LSD exhibited more pronounced segregation effects, characterized solely by decreases, in contrast to the amphetamines, which also induced increases. Across all substances, seed-based connectivity mostly increased between networks, with LSD demonstrating more pronounced effects than both amphetamines. Finally, while all substances decreased global connectivity in visual areas, compared to placebo, LSD specifically increased global connectivity in the basal ganglia and thalamus. These findings advance our understanding of the distinctive neurobiological effects of psychedelics, prompting further exploration of their therapeutic potential., (© 2024. The Author(s).)
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- 2024
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13. Pharmacological and non-pharmacological predictors of the LSD experience in healthy participants.
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Vizeli P, Studerus E, Holze F, Schmid Y, Dolder PC, Ley L, Straumann I, Becker AM, Müller F, Arikci D, and Liechti ME
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- Humans, Male, Female, Adult, Double-Blind Method, Young Adult, Healthy Volunteers, Heart Rate drug effects, Personality, Middle Aged, Dose-Response Relationship, Drug, Adolescent, Lysergic Acid Diethylamide pharmacology, Lysergic Acid Diethylamide administration & dosage, Hallucinogens administration & dosage, Hallucinogens pharmacology, Cross-Over Studies, Affect drug effects
- Abstract
The pharmacodynamic effects of lysergic acid diethylamide (LSD) are diverse and different in different individuals. Effects of other psychoactive substances have been shown to be critically influenced by non-pharmacological factors such as personality traits and mood states. The aim of this study was to determine pharmacological and psychological predictors of the LSD effects in healthy human subjects. This analysis is based on nine double-blind, placebo-controlled, cross-over studies with a total of 213 healthy subjects receiving between 25-200 µg LSD. The influence of sex, age, dose, body weight, pharmacogenetic, drug experience, personality, setting, and mood before drug intake on the peak autonomic and total subjective responses to LSD was investigated using multiple linear mixed effects models and Least Absolute Shrinkage and Selection Operator regression. Results were adjusted for LSD dose and corrected for multiple testing. LSD dose emerged as the most influential predictor, exhibiting a positive correlation with most response variables. Pre-drug mental states such as "Well-Being", "Emotional Excitability", and "Anxiety" were also important predictor for a range of subjective effects but also heart rate and body temperature. The trait "Openness to Experiences" was positively correlated with elevated ratings in "Oceanic Boundlessness" and mystical-type effects. Previous experiences with hallucinogens have been negatively associated with the overall altered state of consciousness and particularly with "Anxious Ego Dissolution". Acute anxiety negatively correlated with the genetically determined functionality of the Cytochrome 2D6 enzyme. In summary, besides the amount of drug consumed, non-pharmacological factors such as personal traits and current mood also significantly predicted the subjective drug experience. Sex and body weight were not significant factors in influencing the drug experience., (© 2024. The Author(s).)
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- 2024
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14. LSD-assisted therapy in patients with anxiety: open-label prospective 12-month follow-up.
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Holze F, Gasser P, Müller F, Strebel M, and Liechti ME
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- Humans, Male, Female, Adult, Follow-Up Studies, Middle Aged, Prospective Studies, Double-Blind Method, Cross-Over Studies, Treatment Outcome, Young Adult, Psychiatric Status Rating Scales, Lysergic Acid Diethylamide administration & dosage, Lysergic Acid Diethylamide pharmacology, Hallucinogens administration & dosage, Hallucinogens therapeutic use, Anxiety Disorders drug therapy
- Abstract
Background: Anxiety disorders are a major public health burden with limited treatment options., Aims: We investigated the long-term safety and efficacy of lysergic acid diethylamide (LSD)-assisted therapy in patients with anxiety with or without life-threatening illness., Method: This study was an a priori -planned long-term follow-up of an investigator-initiated, two-centre trial that used a double-blind, placebo-controlled, two-period, random-order, crossover design with two sessions with either oral LSD (200 μg) or placebo per period. Participants ( n = 39) were followed up 1 year after the end-of-study visit to assess symptoms of anxiety, depression and long-term effects of psychedelics using Spielberger's State-Trait Anxiety Inventory-Global (STAI-G), the Beck Depression Inventory (BDI), the Persisting Effects Questionnaire and measures of personality traits using the NEO - Five-Factor Inventory., Results: Participants reported a sustained reduction of STAI-G scores compared with baseline (least square means (95% CI) = -21.6 (-32.7, -10.4), d = 1.04, P < 0.001, for those who received LSD in the first period (94 weeks after the last LSD treatment) and -16.5 (-26.2, -6.8), d = 1.02, P < 0.05, for those who received LSD in the second period (68 weeks after the last LSD treatment)). Similar effects were observed for comorbid depression with change from baseline BDI scores of -8.1 (-13.2, -3.1), d = 0.71, P < 0.01, and -8.9 (-12.9, -4.9), d = 1.21, P < 0.01, for the LSD-first and placebo-first groups, respectively. Personality trait neuroticism decreased ( P < 0.0001) and trait extraversion increased ( P < 0.01) compared with study inclusion. Individuals attributed positive long-term effects to the psychedelic experience., Conclusions: Patients reported sustained long-term effects of LSD-assisted therapy for anxiety.
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- 2024
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15. Pharmacological Properties of Psychedelics with a Special Focus on Potential Harms.
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Holze F, Liechti ME, and Müller F
- Abstract
Psychedelics are a group of substances within the heterogeneous class of hallucinogenic drugs. Via binding to the serotonin (5-HT) 2A receptor, psychedelics exert profound alterations in various mental domains, including sensation, cognition, emotions, and self-perception. Psychedelics comprise phenethylamines (e.g., mescaline), tryptamines (e.g., psilocybin), and ergolines (e.g., LSD). These drugs have been used recreationally for decades but have also regained attention as potential treatments for various psychiatric as well as neurological illnesses. While psychedelics are generally considered to be relatively safe from a physiological standpoint, especially when compared to other recreational drugs, they are not without risks. The main safety concerns are lasting psychological adverse reactions such as persisting anxiety, dissociation, or flashbacks.This chapter provides a comprehensive overview of the pharmacology of classic psychedelics, including their origins, psychological and autonomic effects, interactions, and potential risks and side effects. Furthermore, the origin, dosing, and consumption methods are discussed. It differentiates psychedelics from other psychoactive drugs, such as MDMA and ketamine, and elaborates on their distinct receptor profiles. Overall, this chapter provides an overview of the pharmacological underpinnings necessary for understanding the harms caused by psychedelic drugs., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)
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- 2024
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16. Psychedelics in Medicine: Can Evidence Keep Up With Enthusiasm?
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de Wit H, Holze F, and Preller KH
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- Humans, Hallucinogens pharmacology
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- 2024
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17. Serotonergic Psychedelics: A Comparative Review of Efficacy, Safety, Pharmacokinetics, and Binding Profile.
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Holze F, Singh N, Liechti ME, and D'Souza DC
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- Humans, Serotonin 5-HT2 Receptor Agonists pharmacology, Serotonin 5-HT2 Receptor Agonists pharmacokinetics, Hallucinogens pharmacokinetics, Hallucinogens pharmacology, Psilocybin pharmacokinetics, Psilocybin pharmacology, Lysergic Acid Diethylamide pharmacology, Lysergic Acid Diethylamide pharmacokinetics
- Abstract
Psychedelic compounds, including psilocybin, LSD (lysergic acid diethylamide), DMT (N,N -dimethyltryptamine), and 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine), all of which are serotonin 2A receptor agonists, are being investigated as potential treatments. This review aims to summarize the current clinical research on these 4 compounds and mescaline to guide future research. Their mechanism(s) of action, pharmacokinetics, pharmacodynamics, efficacy, and safety were reviewed. While evidence for therapeutic indications, with the exception of psilocybin for depression, is still relatively scarce, we noted no differences in psychedelic effects beyond effect duration. Therefore, it remains unclear whether different receptor profiles contribute to the therapeutic potential of these compounds. More research is needed to differentiate these compounds in order to inform which compounds might be best for different therapeutic uses., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
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- 2024
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18. Effective Connectivity of Thalamocortical Interactions Following d-Amphetamine, LSD, and MDMA Administration.
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Avram M, Müller F, Preller KH, Razi A, Rogg H, Korda A, Holze F, Vizeli P, Ley L, Liechti ME, and Borgwardt S
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- Humans, Male, Double-Blind Method, Adult, Female, Young Adult, Neural Pathways drug effects, Connectome, Lysergic Acid Diethylamide pharmacology, Lysergic Acid Diethylamide administration & dosage, N-Methyl-3,4-methylenedioxyamphetamine pharmacology, N-Methyl-3,4-methylenedioxyamphetamine administration & dosage, Thalamus drug effects, Thalamus diagnostic imaging, Thalamus physiology, Magnetic Resonance Imaging, Hallucinogens pharmacology, Hallucinogens administration & dosage, Dextroamphetamine pharmacology, Dextroamphetamine administration & dosage, Cross-Over Studies, Cerebral Cortex drug effects, Cerebral Cortex diagnostic imaging, Cerebral Cortex physiology
- Abstract
Background: While the exploration of serotonergic psychedelics as psychiatric medicines deepens, so does the pressure to better understand how these compounds act on the brain., Methods: We used a double-blind, placebo-controlled, crossover design and administered lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), and d-amphetamine in 25 healthy participants. By using spectral dynamic causal modeling, we mapped substance-induced changes in effective connectivity between the thalamus and different cortex types (unimodal vs. transmodal) derived from a previous study with resting-state functional magnetic resonance imaging data. Due to the distinct pharmacological modes of action of the 3 substances, we were able to investigate specific effects mainly driven by different neurotransmitter systems on thalamocortical and corticothalamic interactions., Results: Compared with placebo, all 3 substances increased the effective connectivity from the thalamus to specific unimodal cortices, whereas the influence of these cortices on the thalamus was reduced. These results indicate increased bottom-up and decreased top-down information flow between the thalamus and some unimodal cortices. However, for the amphetamines, we found the opposite effects when examining the effective connectivity with transmodal cortices, including parts of the salience network. Intriguingly, LSD increased the effective connectivity from the thalamus to both unimodal and transmodal cortices, indicating a breach in the hierarchical organization of ongoing brain activity., Conclusions: The results advance our knowledge about the action of psychedelics on the brain and refine current models aiming to explain the underlying neurobiological processes., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
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- 2024
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19. Pharmacokinetics, pharmacodynamics and urinary recovery of oral lysergic acid diethylamide administration in healthy participants.
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Holze F, Erne L, Duthaler U, and Liechti ME
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- Humans, Healthy Volunteers, Cross-Over Studies, Double-Blind Method, Administration, Oral, Lysergic Acid Diethylamide pharmacology, Hallucinogens pharmacology
- Abstract
Aims: Lysergic acid diethylamide (LSD) is currently investigated for several neurological and psychiatric illnesses. Various studies have investigated the pharmacokinetics and the pharmacokinetic-pharmacodynamic relationship of LSD in healthy participants, but data on urinary recovery and confirmatory studies are missing., Methods: The present study characterized the pharmacokinetics, pharmacokinetic-pharmacodynamic relationship and urinary recovery of LSD at doses of 85 and 170 μg administered orally in 28 healthy participants. The plasma concentrations and subjective effects of LSD were continuously evaluated over a period of 24 h. Urine was collected during 3 time intervals (0-8, 8-16 and 16-24 h after LSD administration). Pharmacokinetic parameters were determined using compartmental modelling. Concentration-subjective effect relationships were described using pharmacokinetic-pharmacodynamic modelling., Results: Mean (95% confidence interval) maximal LSD concentrations were 1.8 ng/mL (1.6-2.0) and 3.4 ng/mL (3.0-3.8) after the administration of 85 and 170 μg LSD, respectively. Maximal concentrations were achieved on average after 1.7 h. Elimination half-lives were 3.7 h (3.4-4.1) and 4.0 h (3.6-4.4), for 85 and 170 μg LSD, respectively. Only 1% of the administered dose was recovered from urine unchanged within the first 24 h, 16% was eliminated as 2-oxo-3-hydroxy-LSD. Urinary recovery was dose proportional. Mean (±standard deviation) durations of subjective effects were 9.3 ± 3.2 and 11 ± 3.7 h, and maximal effects (any drug effects) were 77 ± 18% and 87 ± 13% after 85 and 170 μg of LSD, respectively., Conclusion: The present novel study validates previous findings. LSD exhibited dose-proportional pharmacokinetics and first-order elimination kinetics and dose-dependent duration and intensity of subjective effects. LSD is extensively metabolized and shows dose-proportional urinary recovery., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
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- 2024
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20. The revival of the psychedelic experience scale: Revealing its extended-mystical, visual, and distressing experiential spectrum with LSD and psilocybin studies.
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Stocker K, Hartmann M, Ley L, Becker AM, Holze F, and Liechti ME
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- Humans, Psilocybin, Reproducibility of Results, Mysticism, Consciousness, Lysergic Acid Diethylamide, Hallucinogens
- Abstract
Background: Research with the Psychedelic Experience Questionnaire/Scale (PES) focuses on questions relating to mystical experience (Mystical Experience Questionnaire (MEQ)). The psychometric potential of the non-MEQ items of the PES remains largely unexplored., Aims: We investigated whether the PES also yields subscales besides the MEQ30 subscales., Methods: Data from 239 PES measurements (140 healthy participants) from six studies with moderate to high doses of lysergic acid diethylamide and/or psilocybin were included. New subscales (with items other than MEQ30) were created and validated as follows: (1) theoretical derivation of candidate items; (2) removal of items with rare experiences; (3) exploratory factor analysis; and (4) confirmatory factor analysis. Correlations of subscales within the PES and between the PES and the 5-Dimensional Altered States of Consciousness Scale (5D-ASC) were performed. In addition, a cluster analysis using all items (except rare experiences) was performed., Results: The reliability of the four original factors of the MEQ30 was confirmed and four additional factors for the non-MEQ items were revealed: paradoxicality, connectedness, visual experience, and distressing experience. The first two additional factors were strongly correlated with the MEQ30 mystical subscale. Adding the new subscales to the MEQ30 subscales increased the explained variance with the 5D-ASC. The cluster analysis confirmed our main results and provided additional insights for future psychedelic psychometrics., Conclusion: The study yields a new validated 6-factor structure for extended mystical experience (MEQ40: MEQ30 + Paradoxicality + Connectedness) and covers psychedelic experience as a whole more comprehensively than has hitherto been possible within a single questionnaire (PES48). The entire PES (PES100) can also be used for further future psychedelic-psychometric research., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M. E. Liechti is a consultant for Mind Medicine Inc.
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- 2024
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21. Acute effects of MDMA and LSD co-administration in a double-blind placebo-controlled study in healthy participants.
- Author
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Straumann I, Ley L, Holze F, Becker AM, Klaiber A, Wey K, Duthaler U, Varghese N, Eckert A, and Liechti ME
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- Male, Humans, Female, Healthy Volunteers, Lysergic Acid Diethylamide pharmacology, Double-Blind Method, Cross-Over Studies, N-Methyl-3,4-methylenedioxyamphetamine pharmacology, Hallucinogens pharmacology
- Abstract
There is renewed interest in the use of lysergic acid diethylamide (LSD) in psychiatric research and practice. Although acute subjective effects of LSD are mostly positive, negative subjective effects, including anxiety, may occur. The induction of overall positive acute subjective effects is desired in psychedelic-assisted therapy because positive acute experiences are associated with greater therapeutic long-term benefits. 3,4-Methylenedioxymethamphetamine (MDMA) produces marked positive subjective effects and is used recreationally with LSD, known as "candyflipping." The present study investigated whether the co-administration of MDMA can be used to augment acute subjective effects of LSD. We used a double-blind, randomized, placebo-controlled, crossover design with 24 healthy subjects (12 women, 12 men) to compare the co-administration of MDMA (100 mg) and LSD (100 µg) with MDMA and LSD administration alone and placebo. Outcome measures included subjective, autonomic, and endocrine effects and pharmacokinetics. MDMA co-administration with LSD did not change the quality of acute subjective effects compared with LSD alone. However, acute subjective effects lasted longer after LSD + MDMA co-administration compared with LSD and MDMA alone, consistent with higher plasma concentrations of LSD (C
max and area under the curve) and a longer plasma elimination half-life of LSD when MDMA was co-administered. The LSD + MDMA combination increased blood pressure, heart rate, and pupil size more than LSD alone. Both MDMA alone and the LSD + MDMA combination increased oxytocin levels more than LSD alone. Overall, the co-administration of MDMA (100 mg) did not improve acute effects or the safety profile of LSD (100 µg). The combined use of MDMA and LSD is unlikely to provide relevant benefits over LSD alone in psychedelic-assisted therapy. Trial registration: ClinicalTrials.gov identifier: NCT04516902., (© 2023. American College of Neuropsychopharmacology.)- Published
- 2023
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22. Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants.
- Author
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Ley L, Holze F, Arikci D, Becker AM, Straumann I, Klaiber A, Coviello F, Dierbach S, Thomann J, Duthaler U, Luethi D, Varghese N, Eckert A, and Liechti ME
- Subjects
- Humans, Mescaline pharmacology, Lysergic Acid Diethylamide pharmacology, Cross-Over Studies, Healthy Volunteers, Psilocybin pharmacology, Hallucinogens pharmacology
- Abstract
Mescaline, lysergic acid diethylamide (LSD), and psilocybin are classic serotonergic psychedelics. A valid, direct comparison of the effects of these substances is lacking. The main goal of the present study was to investigate potential pharmacological, physiological and phenomenological differences at psychoactive-equivalent doses of mescaline, LSD, and psilocybin. The present study used a randomized, double-blind, placebo-controlled, cross-over design to compare the acute subjective effects, autonomic effects, and pharmacokinetics of typically used, moderate to high doses of mescaline (300 and 500 mg), LSD (100 µg), and psilocybin (20 mg) in 32 healthy participants. A mescaline dose of 300 mg was used in the first 16 participants and 500 mg was used in the subsequent 16 participants. Acute subjective effects of 500 mg mescaline, LSD, and psilocybin were comparable across various psychometric scales. Autonomic effects of 500 mg mescaline, LSD, and psilocybin were moderate, with psilocybin causing a higher increase in diastolic blood pressure compared with LSD, and LSD showing a trend toward an increase in heart rate compared with psilocybin. The tolerability of mescaline, LSD, and psilocybin was comparable, with mescaline at both doses inducing slightly more subacute adverse effects (12-24 h) than LSD and psilocybin. Clear distinctions were seen in the duration of action between the three substances. Mescaline had the longest effect duration (mean: 11.1 h), followed by LSD (mean: 8.2 h), and psilocybin (mean: 4.9 h). Plasma elimination half-lives of mescaline and LSD were similar (approximately 3.5 h). The longer effect duration of mescaline compared with LSD was due to the longer time to reach maximal plasma concentrations and related peak effects. Mescaline and LSD, but not psilocybin, enhanced circulating oxytocin. None of the substances altered plasma brain-derived neurotrophic factor concentrations. In conclusion, the present study found no evidence of qualitative differences in altered states of consciousness that were induced by equally strong doses of mescaline, LSD, and psilocybin. The results indicate that any differences in the pharmacological profiles of mescaline, LSD, and psilocybin do not translate into relevant differences in the subjective experience. ClinicalTrials.gov identifier: NCT04227756., (© 2023. The Author(s).)
- Published
- 2023
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23. Oxytocin in response to MDMA provocation test in patients with arginine vasopressin deficiency (central diabetes insipidus): a single-centre, case-control study with nested, randomised, double-blind, placebo-controlled crossover trial.
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Atila C, Holze F, Murugesu R, Rommers N, Hutter N, Varghese N, Sailer CO, Eckert A, Heinrichs M, Liechti ME, and Christ-Crain M
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- Humans, Oxytocin, Cross-Over Studies, Case-Control Studies, Double-Blind Method, Arginine, N-Methyl-3,4-methylenedioxyamphetamine adverse effects, Diabetes Insipidus, Neurogenic, Diabetes Mellitus
- Abstract
Background: Disruptions of the hypothalamic-pituitary axis can cause an arginine vasopressin deficiency, also known as central diabetes insipidus. Patients with this condition are at high risk of additional oxytocin deficiency owing to the close anatomical proximity of oxytocin-producing neurons; however, no conclusive evidence for such a deficiency has been reported. We aimed to use 3,4-methylenedioxymethamphetamine (MDMA, also known as ecstasy), a strong activator of the central oxytocinergic system, as a biochemical and psychoactive provocation test to investigate oxytocin deficiency in patients with arginine vasopressin deficiency (central diabetes insipidus)., Methods: This single-centre, case-control study with nested, randomised, double-blind, placebo-controlled crossover trial included patients with arginine vasopressin deficiency (central diabetes insipidus) and healthy controls (matched 1:1 by age, sex, and BMI) and was conducted at the University Hospital Basel, Basel, Switzerland. We used block randomisation to assign participants to receive either a single oral dose of MDMA (100 mg) or placebo in the first experimental session; patients received the opposite treatment at the next session, with a wash-out period of at least 2 weeks between the two sessions. Participants and investigators assessing the outcomes were masked to assignment. Oxytocin concentrations were measured at 0, 90, 120, 150, 180, and 300 min after MDMA or placebo. The primary outcome was the area under the plasma oxytocin concentration curve (AUC) after drug intake. The AUC was compared between groups and conditions using a linear mixed-effects model. Subjective drug effects were assessed throughout the study using ten-point visual analogue scales. Acute adverse effects were assessed before and 360 min after drug intake using a 66-item list of complaints. This trial is registered with ClinicalTrials.gov, NCT04648137., Findings: Between Feb 1, 2021, and May 1, 2022, we recruited 15 patients with arginine vasopressin deficiency (central diabetes insipidus) and 15 healthy controls. All participants completed the study and were included in the analyses. In healthy controls, median plasma oxytocin concentration was 77 pg/mL (IQR 59-94) at baseline and increased by 659 pg/mL (355-914) in response to MDMA, resulting in an AUC of 102 095 pg/mL (41 782-129 565); in patients, baseline oxytocin concentration was 60 pg/mL (51-74) and only slightly increased by 66 pg/mL (16-94) in response to MDMA, resulting in an AUC of 6446 pg/mL (1291-11 577). The effect of MDMA on oxytocin was significantly different between groups: the AUC for oxytocin was 82% (95% CI 70-186) higher in healthy controls than in patients (difference 85 678 pg/mL [95% CI 63 356-108 000], p<0·0001). The increase in oxytocin in healthy controls was associated with typical strong subjective prosocial, empathic, and anxiolytic effects, whereas only minimal subjective effects were observed in patients, in agreement with the lack of increase in oxytocin concentrations. The most frequently reported adverse effects were fatigue (eight [53%] healthy controls and eight [53%] patients), lack of appetite (ten [67%] healthy controls and eight [53%] patients), lack of concentration (eight [53%] healthy controls and seven [47%] patients), and dry mouth (eight [53%] healthy controls and eight [53%] patients). In addition, two (13%) healthy controls and four (27%) patients developed transient mild hypokalaemia., Interpretation: These findings are highly suggestive of clinically meaningful oxytocin deficiency in patients with arginine vasopressin deficiency (central diabetes insipidus), laying the groundwork for a new hypothalamic-pituitary disease entity., Funding: Swiss National Science Foundation, Swiss Academy of Medical Sciences, and the G&J Bangerter-Rhyner Foundation., Competing Interests: Declaration of interests MEL has received consulting and license fees and funding from MindMed for patents and knowledge related to MDMA; the received fees and funding are not related to the present study. MEL owns stocks of MindMed. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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24. The effect of lysergic acid diethylamide (LSD) on whole-brain functional and effective connectivity.
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Bedford P, Hauke DJ, Wang Z, Roth V, Nagy-Huber M, Holze F, Ley L, Vizeli P, Liechti ME, Borgwardt S, Müller F, and Diaconescu AO
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- Humans, Brain, Brain Mapping methods, Neural Pathways physiology, Lysergic Acid Diethylamide pharmacology, Hallucinogens pharmacology
- Abstract
Psychedelics have emerged as promising candidate treatments for various psychiatric conditions, and given their clinical potential, there is a need to identify biomarkers that underlie their effects. Here, we investigate the neural mechanisms of lysergic acid diethylamide (LSD) using regression dynamic causal modelling (rDCM), a novel technique that assesses whole-brain effective connectivity (EC) during resting-state functional magnetic resonance imaging (fMRI). We modelled data from two randomised, placebo-controlled, double-blind, cross-over trials, in which 45 participants were administered 100 μg LSD and placebo in two resting-state fMRI sessions. We compared EC against whole-brain functional connectivity (FC) using classical statistics and machine learning methods. Multivariate analyses of EC parameters revealed predominantly stronger interregional connectivity and reduced self-inhibition under LSD compared to placebo, with the notable exception of weakened interregional connectivity and increased self-inhibition in occipital brain regions as well as subcortical regions. Together, these findings suggests that LSD perturbs the Excitation/Inhibition balance of the brain. Notably, whole-brain EC did not only provide additional mechanistic insight into the effects of LSD on the Excitation/Inhibition balance of the brain, but EC also correlated with global subjective effects of LSD and discriminated experimental conditions in a machine learning-based analysis with high accuracy (91.11%), highlighting the potential of using whole-brain EC to decode or predict subjective effects of LSD in the future., (© 2023. The Author(s).)
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- 2023
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25. Acute effects of intravenous DMT in a randomized placebo-controlled study in healthy participants.
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Vogt SB, Ley L, Erne L, Straumann I, Becker AM, Klaiber A, Holze F, Vandersmissen A, Mueller L, Duthaler U, Rudin D, Luethi D, Varghese N, Eckert A, and Liechti ME
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- Humans, Healthy Volunteers, Administration, Intravenous, Anxiety, N,N-Dimethyltryptamine, Hallucinogens
- Abstract
N,N-dimethyltryptamine (DMT) is distinct among classic serotonergic psychedelics because of its short-lasting effects when administered intravenously. Despite growing interest in the experimental and therapeutic use of intravenous DMT, data are lacking on its clinical pharmacology. We conducted a double-blind, randomized, placebo-controlled crossover trial in 27 healthy participants to test different intravenous DMT administration regimens: placebo, low infusion (0.6 mg/min), high infusion (1 mg/min), low bolus + low infusion (15 mg + 0.6 mg/min), and high bolus + high infusion (25 mg + 1 mg/min). Study sessions lasted for 5 h and were separated by at least 1 week. Participant's lifetime use of psychedelics was ≤20 times. Outcome measures included subjective, autonomic, and adverse effects, pharmacokinetics of DMT, and plasma levels of brain-derived neurotropic factor (BDNF) and oxytocin. Low (15 mg) and high (25 mg) DMT bolus doses rapidly induced very intense psychedelic effects that peaked within 2 min. DMT infusions (0.6 or 1 mg/min) without a bolus induced slowly increasing and dose-dependent psychedelic effects that reached plateaus after 30 min. Both bolus doses produced more negative subjective effects and anxiety than infusions. After stopping the infusion, all drug effects rapidly decreased and completely subsided within 15 min, consistent with a short early plasma elimination half-life (t
1/2α ) of 5.0-5.8 min, followed by longer late elimination (t1/2β = 14-16 min) after 15-20 min. Subjective effects of DMT were stable from 30 to 90 min, despite further increasing plasma concentrations, thus indicating acute tolerance to continuous DMT administration. Intravenous DMT, particularly when administered as an infusion, is a promising tool for the controlled induction of a psychedelic state that can be tailored to the specific needs of patients and therapeutic sessions.Trial registration: ClinicalTrials.gov identifier: NCT04353024., (© 2023. The Author(s).)- Published
- 2023
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26. Pharmacokinetics and Pharmacodynamics of Oral Psilocybin Administration in Healthy Participants.
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Holze F, Becker AM, Kolaczynska KE, Duthaler U, and Liechti ME
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- Humans, Healthy Volunteers, Administration, Oral, Dose-Response Relationship, Drug, Psilocybin pharmacology
- Abstract
Psilocybin is being investigated as a potential treatment for psychiatric and neurological disorders. Only a few studies have evaluated the pharmacokinetics (PKs) of psilocybin and have used body weight-adjusted dosing. Data on PKs and the PK-pharmacodynamic (PD) relationship of fixed doses that are commonly used are unavailable. The present study characterized the PKs and PK-PD relationship of 15, 25, and 30 mg of orally administered psilocybin in 28, 23, and 28 healthy subjects, respectively. Plasma levels of unconjugated psilocin (the psychoactive metabolite of psilocybin) and corresponding subjective effects were repeatedly assessed up to 24 hours. PK parameters were determined using compartmental modeling. Concentration-subjective effect relationships were described using PK-PD modeling. Mean (95% confidence interval) maximal psilocin concentrations were 11 ng/mL (10-13), 17 ng/mL (16-19), and 21 ng/mL (19-24) after the administration of 15, 25, and 30 mg psilocybin, respectively. Maximal concentrations were reached after an average of 2 hours. Elimination half-lives were 1.8 hours (1.7-2.0), 1.4 hours (1.2-1.7), and 1.8 hours (1.6-1.9) for 15, 25, and 30 mg psilocybin, respectively. Mean (± SD) durations of subjective effects were 5.6 ± 2.2 hours, 5.5 ± 1.6 hours, and 6.4 ± 2.2 hours, and maximal effects ("any drug" effects) were 58% ± 25%, 73% ± 27%, and 80% ± 18% after 15, 25, and 30 mg psilocybin, respectively. Psilocin exhibited dose-proportional PKs. The duration and intensity of subjective effects were dose-dependent. Body weight did not influence pharmacokinetics or the response to psilocybin. These data may serve as a reference for future clinical trials., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
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- 2023
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27. Ketanserin Reverses the Acute Response to LSD in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Participants.
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Becker AM, Klaiber A, Holze F, Istampoulouoglou I, Duthaler U, Varghese N, Eckert A, and Liechti ME
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- Humans, Ketanserin pharmacology, Lysergic Acid Diethylamide pharmacology, Cross-Over Studies, Brain-Derived Neurotrophic Factor, Healthy Volunteers, Double-Blind Method, Hallucinogens pharmacology
- Abstract
Background: Lysergic acid diethylamide (LSD) is currently being investigated in psychedelic-assisted therapy. LSD has a long duration of acute action of 8-11 hours. It produces its acute psychedelic effects via stimulation of the serotonin 5-hydroxytryptamine-2A (HT2A) receptor. Administration of the 5-HT2A antagonist ketanserin before LSD almost fully blocks the acute subjective response to LSD. However, unclear is whether ketanserin can also reverse the effects of LSD when administered after LSD., Methods: We used a double-blind, randomized, placebo-controlled, crossover design in 24 healthy participants who underwent two 14-hour sessions and received ketanserin (40 mg p.o.) or placebo 1 hour after LSD (100 µg p.o.). Outcome measures included subjective effects, autonomic effects, acute adverse effects, plasma brain-derived neurotrophic factor levels, and pharmacokinetics up to 12 hours., Results: Ketanserin reversed the acute response to LSD, thereby significantly reducing the duration of subjective effects from 8.5 hours with placebo to 3.5 hours. Ketanserin also reversed LSD-induced alterations of mind, including visual and acoustic alterations and ego dissolution. Ketanserin reduced adverse cardiovascular effects and mydriasis that were associated with LSD but had no effects on elevations of brain-derived neurotrophic factor levels. Ketanserin did not alter the pharmacokinetics of LSD., Conclusions: These findings are consistent with an interaction between ketanserin and LSD and the view that LSD produces its psychedelic effects only when occupying 5-HT2A receptors. Ketanserin can effectively be used as a planned or rescue option to shorten and attenuate the LSD experience in humans in research and LSD-assisted therapy., Trial Registry: ClinicalTrials.gov (NCT04558294)., (© The Author(s) 2022. Published by Oxford University Press on behalf of CINP.)
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- 2023
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28. Lysergic Acid Diethylamide-Assisted Therapy in Patients With Anxiety With and Without a Life-Threatening Illness: A Randomized, Double-Blind, Placebo-Controlled Phase II Study.
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Holze F, Gasser P, Müller F, Dolder PC, and Liechti ME
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- Humans, Anxiety Disorders therapy, Double-Blind Method, Cross-Over Studies, Treatment Outcome, Lysergic Acid Diethylamide therapeutic use, Anxiety drug therapy
- Abstract
Background: This study aimed to investigate the efficacy and safety of lysergic acid diethylamide (LSD)-assisted therapy in patients who experienced anxiety with or without association with a life-threatening illness., Methods: The study is an investigator-initiated 2-center trial that used a double-blind, placebo-controlled, 2-period, random-order, crossover design with 2 sessions with either oral LSD (200 μg) or placebo per period. The primary end point was anxiety symptoms 16 weeks after the last treatment session, assessed by the Spielberger State-Trait Anxiety Inventory-Global score in 42 patients. Further outcome measures included ratings for depression symptoms (Beck Depression Inventory and Hamilton Depression Rating Scale, 21-item version) and ratings for acute subjective drug effects. The outcomes for the first period (between-subjects analysis) are primarily shown due to carryover effects., Results: LSD treatment resulted in significant reductions of State-Trait Anxiety Inventory-Global scores up to 16 weeks after treatment (least-square mean [standard error] change from baseline difference = -16.2 [5.8], 95% CI, -27.8 to -4.5, d = -1.18, p = .007). Similar effects were observed for ratings of comorbid depression on the Hamilton Depression Rating Scale, 21-item version (-7.0 [1.9], 95% CI, -10.8 to -3.2, d = -1.1, p = .0004) and the Beck Depression Inventory (-6.1 [2.6], 95% CI, -11.4 to -0.9, d = -0.72, p = .02). Positive acute subjective drug effects and mystical-type experiences correlated with the long-term reductions in anxiety symptoms. Transient, mild, acute untoward effects of LSD treatment were reported by 8 patients (19%). One treatment-related serious adverse event (acute transient anxiety) occurred (2%)., Conclusions: LSD produced long-lasting and notable reductions in anxiety and comorbid depression symptoms up to 16 weeks., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
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- 2023
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29. Characterizing Thalamocortical (Dys)connectivity Following D-Amphetamine, LSD, and MDMA Administration.
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Avram M, Müller F, Rogg H, Korda A, Andreou C, Holze F, Vizeli P, Ley L, Liechti ME, and Borgwardt S
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- Cross-Over Studies, Dextroamphetamine, Double-Blind Method, Humans, Lysergic Acid Diethylamide pharmacology, Hallucinogens pharmacology, Lysergic Acid, N-Methyl-3,4-methylenedioxyamphetamine pharmacology
- Abstract
Background: Patients with psychotic disorders present alterations in thalamocortical intrinsic functional connectivity as measured by resting-state functional magnetic resonance imaging. Specifically, thalamic intrinsic functional connectivity is increased with sensorimotor cortices (hyperconnectivity) and decreased with prefrontal limbic cortices (hypoconnectivity). Psychedelics such as lysergic acid diethlyamide (LSD) elicit similar thalamocortical hyperconnectivity with sensorimotor areas in healthy volunteers. It is unclear whether LSD also induces thalamocortical hypoconnectivity with prefrontal limbic cortices, because current findings are equivocal. 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 intrinsic functional connectivity with 2 brain networks (auditory-sensorimotor and salience networks, corresponding to sensorimotor and prefrontal limbic cortices, respectively), using a double-blind, placebo-controlled, crossover design., Results: All active substances elicited auditory-sensorimotor-thalamic hyperconnectivity compared with 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 the salience network, 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., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
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- 2022
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30. Flashback phenomena after administration of LSD and psilocybin in controlled studies with healthy participants.
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Müller F, Kraus E, Holze F, Becker A, Ley L, Schmid Y, Vizeli P, Liechti ME, and Borgwardt S
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- Diagnostic and Statistical Manual of Mental Disorders, Healthy Volunteers, Humans, Lysergic Acid Diethylamide, Hallucinogens adverse effects, Psilocybin pharmacology
- Abstract
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., (© 2022. The Author(s).)
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- 2022
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31. Safety pharmacology of acute LSD administration in healthy subjects.
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Holze F, Caluori TV, Vizeli P, and Liechti ME
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- Cross-Over Studies, Double-Blind Method, Healthy Volunteers, Heart Rate, Humans, Hallucinogens adverse effects, Lysergic Acid Diethylamide adverse effects
- Abstract
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., (© 2021. The Author(s).)
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- 2022
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32. Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects.
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Holze F, Ley L, Müller F, Becker AM, Straumann I, Vizeli P, Kuehne SS, Roder MA, Duthaler U, Kolaczynska KE, Varghese N, Eckert A, and Liechti ME
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- Double-Blind Method, Female, Healthy Volunteers, Humans, Male, Psilocybin pharmacology, Hallucinogens, Lysergic Acid Diethylamide
- Abstract
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., (© 2022. The Author(s).)
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- 2022
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33. Acute Effects of Psilocybin After Escitalopram or Placebo Pretreatment in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Subjects.
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Becker AM, Holze F, Grandinetti T, Klaiber A, Toedtli VE, Kolaczynska KE, Duthaler U, Varghese N, Eckert A, Grünblatt E, and Liechti ME
- Subjects
- Antidepressive Agents adverse effects, Citalopram adverse effects, Cross-Over Studies, Double-Blind Method, Healthy Volunteers, Humans, Psilocybin adverse effects, Brain-Derived Neurotrophic Factor genetics, Escitalopram
- Abstract
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., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
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- 2022
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34. Correction to: Safety pharmacology of acute LSD administration in healthy subjects.
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Holze F, Caluori TV, Vizeli P, and Liechti ME
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- 2022
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35. Dosing Psychedelics and MDMA.
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Liechti ME and Holze F
- Subjects
- Lysergic Acid Diethylamide pharmacology, Lysergic Acid Diethylamide therapeutic use, Pharmaceutical Preparations, Psilocybin pharmacology, Psilocybin therapeutic use, Hallucinogens pharmacology, Hallucinogens therapeutic use, N-Methyl-3,4-methylenedioxyamphetamine pharmacology
- Abstract
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., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)
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- 2022
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36. Role of the 5-HT 2A Receptor in Acute Effects of LSD on Empathy and Circulating Oxytocin.
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Holze F, Avedisian I, Varghese N, Eckert A, and Liechti ME
- Abstract
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
2A ) receptor by administering 25, 50, 100, and 200 µg LSD alone and 200 µg LSD combined with pretreatment with the 5-HT2A 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-HT2A receptors to induce subjective psychedelic effects. In contrast, LSD-induced oxytocin release may depend on 5-HT2A 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., Competing Interests: ML is a consultant for Mind Medicine, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Holze, Avedisian, Varghese, Eckert and Liechti.)- Published
- 2021
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37. Genetic influence of CYP2D6 on pharmacokinetics and acute subjective effects of LSD in a pooled analysis.
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Vizeli P, Straumann I, Holze F, Schmid Y, Dolder PC, and Liechti ME
- Subjects
- Adult, Clinical Trials, Phase I as Topic, Cross-Over Studies, Double-Blind Method, Female, Hallucinogens administration & dosage, Healthy Volunteers, Humans, Lysergic Acid Diethylamide administration & dosage, Male, Middle Aged, Randomized Controlled Trials as Topic, Cytochrome P-450 CYP2D6 genetics, Hallucinogens pharmacokinetics, Lysergic Acid Diethylamide pharmacokinetics, Pharmacogenomic Variants
- Abstract
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.
- Published
- 2021
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38. A low dose of lysergic acid diethylamide decreases pain perception in healthy volunteers.
- Author
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Ramaekers JG, Hutten N, Mason NL, Dolder P, Theunissen EL, Holze F, Liechti ME, Feilding A, and Kuypers KP
- Subjects
- Adult, Analgesics administration & dosage, Analgesics adverse effects, Analgesics pharmacokinetics, Biological Availability, Cold Temperature, Double-Blind Method, Female, Hallucinogens administration & dosage, Hallucinogens adverse effects, Hallucinogens pharmacokinetics, Healthy Volunteers, Humans, Male, Treatment Outcome, Dose-Response Relationship, Drug, Drug-Related Side Effects and Adverse Reactions prevention & control, Lysergic Acid Diethylamide administration & dosage, Lysergic Acid Diethylamide adverse effects, Lysergic Acid Diethylamide pharmacokinetics, Pain Measurement methods, Pain Perception drug effects, Pain Perception physiology, Pain Threshold drug effects, Pain Threshold psychology
- Abstract
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.
- Published
- 2021
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39. Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide Microdoses in Healthy Participants.
- Author
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Holze F, Liechti ME, Hutten NRPW, Mason NL, Dolder PC, Theunissen EL, Duthaler U, Feilding A, Ramaekers JG, and Kuypers KPC
- Subjects
- Adult, Cross-Over Studies, Dose-Response Relationship, Drug, Double-Blind Method, Female, Hallucinogens administration & dosage, Hallucinogens adverse effects, Hallucinogens blood, Healthy Volunteers, Humans, Linear Models, Lysergic Acid Diethylamide administration & dosage, Lysergic Acid Diethylamide adverse effects, Lysergic Acid Diethylamide blood, Male, Models, Biological, Young Adult, Affect drug effects, Cognition drug effects, Hallucinogens pharmacokinetics, Lysergic Acid Diethylamide pharmacokinetics
- Abstract
"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., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2021
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40. Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects.
- Author
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Holze F, Vizeli P, Ley L, Müller F, Dolder P, Stocker M, Duthaler U, Varghese N, Eckert A, Borgwardt S, and Liechti ME
- Subjects
- Double-Blind Method, Female, Healthy Volunteers, Humans, Ketanserin pharmacology, Male, Hallucinogens pharmacology, Lysergic Acid Diethylamide pharmacology
- Abstract
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
2A ) 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-HT2A receptor activation.- Published
- 2021
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41. MDMA-induced changes in within-network connectivity contradict the specificity of these alterations for the effects of serotonergic hallucinogens.
- Author
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Müller F, Holze F, Dolder P, Ley L, Vizeli P, Soltermann A, Liechti ME, and Borgwardt S
- Subjects
- Double-Blind Method, Humans, Lysergic Acid Diethylamide pharmacology, Magnetic Resonance Imaging, Hallucinogens pharmacology, N-Methyl-3,4-methylenedioxyamphetamine pharmacology
- Abstract
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.
- Published
- 2021
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42. Mood and cognition after administration of low LSD doses in healthy volunteers: A placebo controlled dose-effect finding study.
- Author
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Hutten NRPW, Mason NL, Dolder PC, Theunissen EL, Holze F, Liechti ME, Feilding A, Ramaekers JG, and Kuypers KPC
- Subjects
- Administration, Oral, Adult, Affect physiology, Cognition physiology, Cross-Over Studies, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Reaction Time physiology, Young Adult, Affect drug effects, Cognition drug effects, Hallucinogens administration & dosage, Healthy Volunteers psychology, Lysergic Acid Diethylamide administration & dosage, Reaction Time drug effects
- Abstract
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., Competing Interests: Conflict of interest Authors declare no conflict of interest., (Copyright © 2020. Published by Elsevier B.V.)
- Published
- 2020
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43. Treatment of a Complex Personality Disorder Using Repeated Doses of LSD-A Case Report on Significant Improvements in the Absence of Acute Drug Effects.
- Author
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Müller F, Mühlhauser M, Holze F, Lang UE, Walter M, Liechti ME, and Borgwardt S
- Abstract
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., (Copyright © 2020 Müller, Mühlhauser, Holze, Lang, Walter, Liechti and Borgwardt.)
- Published
- 2020
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44. Low Doses of LSD Acutely Increase BDNF Blood Plasma Levels in Healthy Volunteers.
- Author
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Hutten NRPW, Mason NL, Dolder PC, Theunissen EL, Holze F, Liechti ME, Varghese N, Eckert A, Feilding A, Ramaekers JG, and Kuypers KPC
- Abstract
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., Competing Interests: The authors declare no competing financial interest.
- Published
- 2020
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45. 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.
- Author
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Steuer AE, Kaelin D, Boxler MI, Eisenbeiss L, Holze F, Vizeli P, Czerwinska J, Dargan PI, Abbate V, Liechti ME, and Kraemer T
- Abstract
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.
- Published
- 2020
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- View/download PDF
46. Distinct acute effects of LSD, MDMA, and D-amphetamine in healthy subjects.
- Author
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Holze F, Vizeli P, Müller F, Ley L, Duerig R, Varghese N, Eckert A, Borgwardt S, and Liechti ME
- Subjects
- Adult, Affect drug effects, Affect physiology, Consciousness physiology, Cross-Over Studies, Double-Blind Method, Female, Healthy Volunteers, Humans, Male, Middle Aged, Retrospective Studies, Time Factors, Central Nervous System Stimulants administration & dosage, Consciousness drug effects, Dextroamphetamine administration & dosage, Hallucinogens administration & dosage, Lysergic Acid Diethylamide administration & dosage, N-Methyl-3,4-methylenedioxyamphetamine administration & dosage
- Abstract
Lysergic acid diethylamide (LSD) is a classic psychedelic, 3,4-methylenedioxymethamphetamine (MDMA) is an empathogen, and D-amphetamine is a classic stimulant. All three substances are used recreationally. LSD and MDMA are being investigated as medications to assist psychotherapy, and D-amphetamine is used for the treatment of attention-deficit/hyperactivity disorder. All three substances induce distinct acute subjective effects. However, differences in acute responses to these prototypical psychoactive substances have not been characterized in a controlled study. We investigated the acute autonomic, subjective, and endocrine effects of single doses of LSD (0.1 mg), MDMA (125 mg), D-amphetamine (40 mg), and placebo in a randomized, double-blind, cross-over study in 28 healthy subjects. All of the substances produced comparable increases in hemodynamic effects, body temperature, and pupil size, indicating equivalent autonomic responses at the doses used. LSD and MDMA increased heart rate more than D-amphetamine, and D-amphetamine increased blood pressure more than LSD and MDMA. LSD induced significantly higher ratings on the 5 Dimensions of Altered States of Consciousness scale and Mystical Experience Questionnaire than MDMA and D-amphetamine. LSD also produced greater subjective drug effects, ego dissolution, introversion, emotional excitation, anxiety, and inactivity than MDMA and D-amphetamine. LSD also induced greater impairments in subjective ratings of concentration, sense of time, and speed of thinking compared with MDMA and D-amphetamine. MDMA produced greater ratings of good drug effects, liking, high, and ego dissolution compared with D-amphetamine. D-Amphetamine increased ratings of activity and concentration compared with LSD. MDMA but not LSD or D-amphetamine increased plasma concentrations of oxytocin. None of the substances altered plasma concentrations of brain-derived neurotrophic factor. These results indicate clearly distinct acute effects of LSD, MDMA, and D-amphetamine and may assist the dose-finding in substance-assisted psychotherapy research.
- Published
- 2020
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47. Pharmacokinetics and subjective effects of a novel oral LSD formulation in healthy subjects.
- Author
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Holze F, Duthaler U, Vizeli P, Müller F, Borgwardt S, and Liechti ME
- Subjects
- Administration, Oral, Adult, Area Under Curve, Cross-Over Studies, Double-Blind Method, Female, Half-Life, Hallucinogens pharmacokinetics, Hallucinogens pharmacology, Humans, Lysergic Acid Diethylamide analogs & derivatives, Lysergic Acid Diethylamide pharmacokinetics, Lysergic Acid Diethylamide pharmacology, Male, Middle Aged, Hallucinogens administration & dosage, Lysergic Acid Diethylamide administration & dosage
- 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 (C
max ) 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., (© 2019 The British Pharmacological Society.)- Published
- 2019
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48. Alcohol acutely enhances decoding of positive emotions and emotional concern for positive stimuli and facilitates the viewing of sexual images.
- Author
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Dolder PC, Holze F, Liakoni E, Harder S, Schmid Y, and Liechti ME
- Subjects
- Adolescent, Adult, Cross-Over Studies, Double-Blind Method, Female, Humans, Interpersonal Relations, Male, Oxytocin blood, Photic Stimulation, Social Behavior, Young Adult, Alcohol Drinking psychology, Emotions drug effects, Empathy drug effects, Ethanol pharmacology, Sexual Behavior drug effects
- Abstract
Rationale: Social cognition influences social interactions. Alcohol reportedly facilitates social interactions. However, the acute effects of alcohol on social cognition are relatively poorly studied., Methods: We investigated the effects of alcoholic or non-alcoholic beer on emotion recognition, empathy, and sexual arousal using the dynamic face emotion recognition task (FERT), Multifaceted Empathy Test (MET), and Sexual Arousal Task (SAT) in a double-blind, random-order, cross-over study in 60 healthy social drinkers. We also assessed subjective effects using visual analog scales (VASs), blood alcohol concentrations, and plasma oxytocin levels., Results: Alcohol increased VAS ratings of stimulated, happy, talkative, open, and want to be with others. The subjective effects of alcohol were greater in participants with higher trait inhibitedness. Alcohol facilitated the recognition of happy faces on the FERT and enhanced emotional empathy for positive stimuli on the MET, particularly in participants with low trait empathy. Pictures of explicit sexual content were rated as less pleasant than neutral pictures after non-alcoholic beer but not after alcoholic beer. Explicit sexual pictures were rated as more pleasant after alcoholic beer compared with non-alcoholic beer, particularly in women. Alcohol did not alter the levels of circulating oxytocin., Conclusions: Alcohol biased emotion recognition toward better decoding of positive emotions and increased emotional concern for positive stimuli. No support was found for a modulatory role of oxytocin. Alcohol also facilitated the viewing of sexual images, consistent with disinhibition, but it did not actually enhance sexual arousal. These effects of alcohol on social cognition likely enhance sociability., Trial Registration: www.clinicaltrials.gov/ct2/show/NCT02318823.
- Published
- 2017
- Full Text
- View/download PDF
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