Neuropsychopharmacology
November 16, 2019
Friederike Holze, Patrick Vizeli, Felix Müller et al.
250 citations
LSD, MDMA, and d-amphetamine all increased heart rate, blood pressure, body temperature, and pupil size, but LSD produced the strongest alterations in consciousness, mystical experiences, ego dissolution, and emotional excitation. MDMA increased feelings of good drug effects, liking, and high more than d-amphetamine, and only MDMA raised oxytocin levels. d-Amphetamine boosted activity and concentration relative to LSD. None of the substances changed brain-derived neurotrophic factor. The findings highlight distinct subjective and endocrine profiles that may inform dosing in psychedelic-assisted therapy.
Neuropsychopharmacology
October 15, 2020
Friederike Holze, Patrick Vizeli, Laura Ley et al.
243 citations
Lysergic acid diethylamide (LSD) produces dose-dependent subjective effects starting at 25 µg, with a ceiling for good drug effects at 100 µg, while ego dissolution and anxiety increase further at 200 µg. The average duration of subjective effects lengthens from 6.7 to 11 hours across the 25–200 µg range. LSD moderately raises blood pressure and heart rate. The serotonin 5-HT2A receptor antagonist ketanserin (40 mg) given before 200 µg LSD prevents the response, indicating that LSD's full psychedelic effects are primarily mediated by 5-HT2A receptor activation. These results assist dose finding for future LSD research.
Neuropsychopharmacology
February 25, 2022
Friederike Holze, Laura Ley, Felix Müller et al.
223 citations
In healthy volunteers, 100 and 200 micrograms of LSD and 30 milligrams of psilocybin produce comparable subjective effects, including alterations of mind that are qualitatively and quantitatively very similar. The 15 milligram psilocybin dose produces clearly weaker subjective effects. The 200 microgram dose of LSD induces higher ratings of ego-dissolution, impairments in control and cognition, and anxiety than the 100 microgram dose. LSD at both doses has clearly longer effect durations than psilocybin. Psilocybin increases blood pressure more than LSD, whereas LSD increases heart rate more than psilocybin, though both show comparable overall cardiostimulant properties. Any differences between LSD and psilocybin appear dose-dependent rather than substance-dependent, except for the differential effects on heart rate and blood pressure.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
October 1, 2023
Laura Ley, Friederike Holze, Denis Arikci et al.
127 citations
At equally strong doses, the classic psychedelics mescaline, LSD, and psilocybin produce comparable subjective experiences, with no evidence of qualitative differences in altered states of consciousness. Autonomic effects were moderate; psilocybin increased diastolic blood pressure more than LSD, while LSD showed a trend toward higher heart rate than psilocybin. Mescaline had the longest effect duration (mean 11.1 hours), followed by LSD (8.2 hours) and psilocybin (4.9 hours). Mescaline and LSD, but not psilocybin, raised circulating oxytocin. None altered brain-derived neurotrophic factor. Tolerability was similar, though mescaline caused slightly more subacute adverse effects 12–24 hours later.
Translational psychiatry
May 23, 2023
Severin B Vogt, Laura Ley, Livio Erne et al.
85 citations
Intravenous DMT can produce a psychedelic state that is short-lasting and controllable. A double-blind, placebo-controlled crossover trial with 27 healthy participants tested five DMT regimens: low infusion (0.6 mg/min), high infusion (1 mg/min), low bolus plus low infusion (15 mg + 0.6 mg/min), and high bolus plus high infusion (25 mg + 1 mg/min). Bolus doses induced very intense effects within 2 minutes, with more negative feelings and anxiety than infusions. Infusions produced slowly increasing, dose-dependent effects that plateaued after 30 minutes. All effects subsided within 15 minutes of stopping the infusion. Acute tolerance developed, with stable subjective effects from 30 to 90 minutes despite rising plasma concentrations. Intravenous DMT infusion is a promising tool for tailored psychedelic therapy.
Psychopharmacology
January 25, 2022
Felix Müller, Elias Kraus, Friederike Holze et al.
64 citations
Up to 9.2% of healthy volunteers reported reoccurring drug-like experiences after taking LSD or psilocybin in controlled studies, but none met the criteria for hallucinogen-persisting perception disorder (HPPD). The experiences were mostly mild, visual, brief, and perceived as neutral or pleasant, with no impairment in daily life. Distressing experiences occurred in two subjects but subsided spontaneously. The findings suggest that flashbacks are not a clinically relevant problem in controlled settings with healthy participants.
Journal of Psychopharmacology
March 30, 2021
Erich Studerus, Patrick Vizeli, Samuel Harder et al.
51 citations
The acute response to MDMA (ecstasy) is shaped by both drug concentration in the blood and personal characteristics. Pooling data from 10 placebo-controlled studies with 194 healthy adults, the strongest predictor of effects was MDMA plasma level. After adjusting for dose by body weight, higher activity of the enzyme CYP2D6 predicted lower MDMA concentrations. People scoring high in openness to experience reported more closeness, less general inactivation, and stronger altered states of consciousness. Those with high neuroticism or trait anxiety were more likely to have unpleasant or anxious reactions. These findings highlight that both pharmacological and non-pharmacological factors influence MDMA's effects, which may inform its therapeutic use.
Neuropsychopharmacology
April 25, 2023
Peter Bedford, Daniel J. Hauke, Zheng Wang et al.
43 citations
Lysergic acid diethylamide (LSD) predominantly strengthens interregional connections and reduces self-inhibition across the brain, except in occipital and subcortical regions where connections weaken and self-inhibition increases. These patterns suggest LSD perturbs the brain's excitation/inhibition balance. Whole-brain effective connectivity, assessed via regression dynamic causal modelling of resting-state fMRI data from 45 participants in two placebo-controlled trials, discriminated LSD from placebo with 91.11% accuracy and correlated with global subjective effects, indicating potential for decoding subjective experiences.
Biological Psychiatry Cognitive Neuroscience and Neuroimaging
April 29, 2022
Mihai Avram, Felix Müller, Helena Rogg et al.
43 citations
Psychedelics, empathogens, and psychostimulants produce increased connectivity between the thalamus and sensorimotor areas of the brain, a pattern similar to that observed in individuals with psychotic disorders. This suggests a shared neural mechanism across these substances and certain psychiatric conditions, linking altered thalamocortical communication to changes in perception and behavior.
Neuropsychopharmacology
November 20, 2020
Felix Müller, Friederike Holze, Patrick C. Dolder et al.
43 citations
The non-hallucinogenic drug MDMA reduces functional connectivity within several resting-state brain networks, including the default mode network, visual networks, and the sensorimotor network. These decreases closely match those previously reported for hallucinogenic drugs like LSD. The findings suggest that such connectivity changes are not specific to serotonergic hallucinogens but can be induced by monoaminergic stimulation without marked subjective drug effects. However, alterations within the default mode network may help explain the antidepressant effects of some of these substances.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
December 1, 2023
Isabelle Straumann, Laura Ley, Friederike Holze et al.
41 citations
Co-administering MDMA (100 mg) with LSD (100 µg) does not improve the quality of the acute subjective effects compared with LSD alone in healthy adults. The combination prolongs the duration of subjective effects and increases blood pressure, heart rate, and pupil size more than LSD alone. Oxytocin levels rise more with MDMA alone or the combination than with LSD alone. The findings suggest that combining MDMA with LSD offers no relevant benefits over LSD alone for psychedelic-assisted therapy.
Molecular psychiatry
April 1, 2025
Mihai Avram, Lydia Fortea, Lea Wollner et al.
26 citations
Lysergic acid diethylamide (LSD), d-amphetamine, and MDMA each reduce the integrity (within-network connectivity) of several brain networks, with LSD uniquely reducing integrity in the default-mode network. Contrary to expectations, amphetamines reduced integrity in more networks than LSD. LSD produced more pronounced decreases in between-network segregation, while amphetamines also induced increases. Seed-based connectivity mostly increased between networks across all substances, with LSD showing stronger effects than both amphetamines. All substances decreased global connectivity in visual areas, but LSD specifically increased global connectivity in the basal ganglia and thalamus. These findings clarify distinctive neurobiological effects of psychedelics and support further investigation of their therapeutic potential.
Neuroscience Applied
January 1, 2024
Isabelle Straumann, Friederike Holze, Laura Ley et al.
24 citations
A pooled analysis of three randomized crossover studies with 85 healthy participants and 113 single-dose administrations of psilocybin (15, 20, 25, and 30 mg) examined safety. The 20, 25, and 30 mg doses produced stronger subjective effects than 15 mg, and all doses induced higher 'good drug effects' than 'bad drug effects.' Only 25 and 30 mg increased anxiety. Autonomic effects were moderate: tachycardia occurred with 7% of administrations, and body temperature above 38°C rose with dose, reaching 32% at 30 mg. Kidney and liver function remained unchanged. Five participants (6%) reported transient flashbacks, and no serious adverse reactions occurred. The findings indicate that a single psilocybin dose is safe regarding acute psychological and physical harm in healthy participants under controlled conditions.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
December 15, 2022
Dino Luethi, Karolina E Kolaczynska, Severin B Vogt et al.
24 citations
A new LC-MS/MS method accurately measures the psychedelic compound DMT and its major metabolites IAA and DMT-NO in human plasma. The assay uses a simple protein precipitation step, a pentafluorophenyl column for separation, and detects analytes via mass spectrometry. Calibration ranges cover 0.25–250 ng/mL for DMT, 0.1–100 ng/mL for DMT-NO, and 25–25,000 ng/mL for IAA (using a labeled internal standard to account for endogenous IAA). Accuracy ranged from 93% to 113% with precision ≤11%. The method successfully determined pharmacokinetic parameters in participants receiving a 90-minute intravenous infusion of 1 mg/min DMT. It is easy to use, has a short run time, and is suitable for clinical DMT pharmacokinetic and metabolism studies.
Journal of Pharmaceutical and Biomedical Analysis
August 1, 2022
Jan Thomann, Laura Ley, Aaron Klaiber et al.
23 citations
A bioanalytical method using ultra-high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed and validated to rapidly quantify mescaline and its metabolites (TMPAA, NAM, and 4-desmethyl mescaline) in human plasma. The single-step protein precipitation extraction achieved complete recovery (≥98.3%) with minor matrix effects (≤7.58%). Intra-assay accuracy ranged from 84.9% to 106%, and precision was ≤7.33%. The method's sensitivity allowed lower limits of quantification of 12.5 ng/mL for mescaline and TMPAA, and 1.25 ng/mL for NAM, sufficient for clinical pharmacokinetic studies. However, 4-desmethyl mescaline could not be selectively quantified due to interference from another metabolite. The method is reliable and easy-to-use for forensic and clinical pharmacokinetic applications.
Journal of Psychopharmacology
October 31, 2023
Kurt Stocker, Matthias Hartmann, Laura Ley et al.
22 citations
A questionnaire that measures psychedelic experiences, the Psychedelic Experience Scale (PES), contains more useful subscales than the well-known Mystical Experience Questionnaire (MEQ30). Analyzing 239 measurements from 140 healthy participants given LSD or psilocybin, researchers identified four additional factors beyond the original four: paradoxicality, connectedness, visual experience, and distressing experience. Paradoxicality and connectedness correlated strongly with the mystical subscale. Adding these new subscales to the MEQ30 increased the variance explained alongside another measure, the 5D-ASC. A cluster analysis supported these findings. The results provide a validated 6-factor structure (MEQ40) covering mystical experience more comprehensively and a broader 48-item version (PES48), with the full 100-item PES available for future research.
Med (New York, N.Y.)
June 4, 2025
Felix Müller, Hannes Zaczek, Anna M Becker et al.
21 citations
In a double-blind, low-dose controlled trial, 61 patients with moderate-to-severe major depressive disorder received supportive psychotherapy and either two high doses (100 μg then 200 μg) or two low doses (25 μg each) of LSD. At the primary endpoint two weeks after the second session, the high-dose group showed a greater average reduction in self-rated depression scores (11.8 points) compared to the low-dose group (3.9 points), a difference that approached but did not reach statistical significance. Clinician-rated scores also favored the high dose, but significance was lost after adjusting for baseline depression severity. Improvements were numerically maintained through 12 weeks. Adverse events were similar between groups. The authors suggest these exploratory results warrant a larger phase 3 trial.
Translational psychiatry
September 4, 2024
Patrick Vizeli, Erich Studerus, Friederike Holze et al.
15 citations
LSD dose is the strongest predictor of the drug's subjective and autonomic effects, but non-pharmacological factors also play a significant role. Pre-drug mood states—such as well-being, emotional excitability, and anxiety—predict subjective effects, heart rate, and body temperature. The personality trait openness to experiences correlates with stronger mystical-type effects and oceanic boundlessness. Prior hallucinogen use is linked to less anxious ego dissolution and a less intense overall altered state. Acute anxiety relates negatively to the functionality of the Cytochrome 2D6 enzyme. Sex and body weight do not significantly influence the drug experience.
Biological psychiatry. Cognitive neuroscience and neuroimaging
May 1, 2024
Mihai Avram, Felix Müller, Katrin H Preller et al.
13 citations
In a double-blind, placebo-controlled, crossover study with 25 healthy participants, LSD, MDMA, and d-amphetamine all increased effective connectivity from the thalamus to specific unimodal cortices while reducing the influence of those cortices back onto the thalamus, indicating stronger bottom-up and weaker top-down information flow. For transmodal cortices, including parts of the salience network, amphetamines showed opposite effects. LSD uniquely increased effective connectivity from the thalamus to both unimodal and transmodal cortices, suggesting a breakdown in the hierarchical organization of brain activity. These findings refine models of how psychedelics alter brain connectivity.
British journal of clinical pharmacology
November 25, 2024
Aaron Klaiber, Mélusine Humbert-Droz, Laura Ley et al.
6 citations
Mescaline doses up to 800 mg appear safe in controlled clinical settings for healthy individuals. In two double-blind, placebo-controlled studies with 48 participants and 96 administrations, positive subjective effects increased with dose and consistently outweighed negative effects. Autonomic effects rose moderately: systolic blood pressure exceeded 180 mmHg in 6% of administrations, heart rate above 100 beats/min occurred in 3%, and body temperature above 38 °C in 5%. Nausea limited higher doses. Kidney and liver function and blood cell counts remained normal. Flashbacks followed 2% of administrations. Adverse effects totaled 51 at 100 mg and 180 at 800 mg.
Journal of psychopharmacology (Oxford, England)
December 26, 2025
Kurt Stocker, Matthias Hartmann, Yasmin Schmid et al.
5 citations
A psychometric revalidation of the Altered States of Consciousness Scale (ASC) using data from 901 questionnaires across 16 psychedelic studies (with LSD, psilocybin, mescaline, and DMT) shows that ten of the eleven subscales can be grouped into three higher-order dimensions—Positive Effects, Distressing Effects, and Perceptual Effects—mirroring the original three-dimensional model but with improved statistical fit. The Anxiety subscale could not be integrated due to floor effects (low anxiety in the sample) but is retained for clinical relevance. The revised scale, 3D-ASCr, is recommended for use with classic serotonergic psychedelics.
Clinical pharmacokinetics
July 14, 2025
Lorenz Mueller, Aaron Klaiber, Laura Ley et al.
4 citations
Mescaline, a classic psychedelic, shows dose-proportional increases in blood concentration and effects after oral administration. Peak levels occur within about 2 hours, with a half-life of 3.5 hours. Effects begin around 1 hour after dosing, with intensity and duration increasing from 13% and 2.8 hours at 100 mg to 89% and 15 hours at 800 mg. About 53% of the dose is excreted unchanged in urine, and 31% as a main metabolite. Oral bioavailability is at least 53%, limited by first-pass metabolism, with renal elimination as the primary clearance route.
Psychopharmacology
March 26, 2025
Laura Ley, Matthias E Liechti, Anna M Becker et al.
3 citations
Healthy volunteers enroll in psychedelic trials primarily out of interest in the substances and the appeal of the study setting, hoping for personal development and transformative experiences. In a series of six double-blind, placebo-controlled trials involving 151 participants, positive experiences were promoted by music, access to nature, and a trusting relationship with the investigator. A sterile hospital environment, lack of investigator support, and investigator-induced discomfort were criticized. Most volunteers felt their expectations were exceeded and would take the substances again, ideally in a natural setting with friends. Four key factors for positive study experiences are a secure interpersonal relationship, an aesthetically pleasing environment, access to nature, and music.
Cell Reports Medicine
May 7, 2026
Mihai Avram, Aurore Menegaux, Felix Müller et al.
1 citation
Lysergic acid diethylamide (LSD) may alleviate depression by altering white matter microstructure in the brain, potentially reflecting enhanced neuroplasticity. In a clinical trial of 61 patients with major depressive disorder, those receiving moderate-to-high doses (100 μg then 200 μg) showed increased fractional anisotropy in several white matter tracts, including the internal and external capsule, sagittal stratum, and fornix/stria terminalis. These microstructural changes correlated with improvements in depressive symptoms measured at 2, 6, and 12 weeks. The findings suggest that LSD-induced white matter changes are linked to antidepressant effects.
International journal of methods in psychiatric research
June 1, 2026
Kurt Stocker, Matthias Hartmann, Frederick S Barrett et al.
The eight-factor structure of the Psychedelic Experience Scale (PES48), which includes the Mystical Experience Questionnaire (MEQ30) and additional factors for paradoxicality, connectedness, visual experience, and distressing experience, is valid for use in English. Analysis of 280 measurements from 145 healthy participants in four placebo-controlled psilocybin studies found that six subscales have high internal consistency, one good, and one acceptable. Both the MEQ30 and MEQ40 models show acceptable to good model fits, with better fits in English than in German. All six MEQ40 scale means were higher in English data, suggesting that the PES48 provides a broader conceptualization of mystical and non-mystical psychedelic experiences, and that setting may influence mystical experience.