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.
Journal of Psychopharmacology
February 21, 2017
Patrick Vizeli, Matthias E. Liechti
142 citations
In nine double-blind, placebo-controlled studies with 166 healthy subjects, single doses of MDMA (75 or 125 mg) produced acute positive subjective effects lasting about 4 hours, with the higher dose yielding stronger 'good drug effect' ratings. Moderate and transient 'bad drug effects' were greater in women than men. MDMA raised systolic blood pressure above 160 mmHg in 33% of subjects, heart rate above 100 beats/min in 29%, and body temperature above 38°C in 19%; these effects were more frequent with the 125 mg dose. Adverse effects were dose-dependent and more common in females. No serious adverse events occurred, and liver or kidney function was unaffected about a month later. MDMA was safe in healthy subjects in a medical setting, but risks are likely higher in patients with cardiovascular disease.
British Journal of Clinical Pharmacology
March 19, 2019
Friederike Holze, Urs Duthaler, Patrick Vizeli et al.
72 citations
After a 100 μg oral dose of LSD, plasma levels peak at about 1.7 hours and decline with a half-life of 3.6 hours. The main metabolite O-H-LSD peaks later, around 5 hours, and has a longer half-life of 5.2 hours. No sex differences in pharmacokinetics were observed. Subjective effects last an average of 8.5 hours, peaking at 2.5 hours. The concentration needed to produce half-maximal effects is 1.0 ng/mL for good effects and 1.9 ng/mL for bad effects, showing that subjective experiences closely track plasma concentrations over time.
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.
Psychopharmacology
September 13, 2021
Friederike Holze, Toya V Caluori, Patrick Vizeli et al.
57 citations
LSD dose-dependently increased subjective, physiologic, and adverse effects in healthy subjects. Positive subjective effects (good drug effect) were more pronounced than negative ones (bad drug effect), with maximal ratings of >50% good drug effects reached in 37%, 91%, 96%, and 91% of administrations at 25, 50, 100, and 200 µg, respectively, versus 0%, 9%, 27%, and 31% for bad drug effects. Physiologic effects were moderate: no systolic blood pressure exceeded 180 mmHg, peak heart rate >100 beats/min occurred in up to 25% of subjects at the highest dose, and peak body temperature >38°C in up to 34%. Kidney and liver function remained unaltered. Six subjects reported transient flashbacks. Single-dose LSD is safe regarding acute psychological and physical harm in healthy subjects in a controlled research setting.
Sci Rep
May 25, 2021
Patrick Vizeli, Isabelle Straumann, Friederike Holze et al.
54 citations
Genetic variation in the CYP2D6 gene significantly affects how the body processes LSD and how strongly people experience its subjective effects. In 81 healthy volunteers from four placebo-controlled trials, individuals with no functional CYP2D6 (poor metabolizers) had about 75% higher blood concentrations of LSD and its main metabolite, longer drug half-lives, and greater alterations of mind with longer subjective effect durations compared to those with functional CYP2D6. Other CYP genes (CYP1A2, CYP2C9, CYP2C19, CYP2B6) showed no influence. These results suggest that pharmacogenetic testing for CYP2D6 may be relevant before LSD-assisted psychotherapy.
Frontiers in Pharmacology
April 29, 2024
Jan Thomann, Oliver V Stoeckmann, Deborah Rudin et al.
52 citations
Psilocybin is rapidly converted to psilocin in the body, which causes psychedelic effects by binding to the 5-HT2A receptor. Psilocin is mainly broken down by glucuronidation or conversion to 4-hydroxyindole-3-acetic acid (4-HIAA). In laboratory experiments with human liver microsomes, about 29% of psilocin was metabolized, while specific enzymes CYP2D6 and CYP3A4 metabolized nearly 100% and 40%, respectively. Monoamine oxidase A produced small amounts of 4-HIAA and 4-hydroxytryptophol (4-HTP), but 4-HTP appeared only in lab tests and neither metabolite showed activity at serotonin receptors. Two new potential metabolites were found: norpsilocin in mice and an oxidized form in humans, though CYP2D6 genotype did not affect psilocin levels in people. These findings help understand drug interactions and psilocybin's therapeutic use.
Pharmacogenetics and Genomics
June 2, 2016
Yasmin Schmid, Patrick Vizeli, Cédric M. Hysek et al.
52 citations
Genetic variants in the CYP2D6 enzyme, which metabolizes MDMA (ecstasy), alter the drug's pharmacokinetics and effects. In a pooled analysis of eight double-blind, placebo-controlled crossover studies involving 139 healthy individuals (70 men, 69 women), people with poor CYP2D6 metabolism had 15% higher peak concentrations of MDMA and 50% higher peak concentrations of its active metabolite, while the inactive metabolite was 50-70% lower, compared to extensive metabolizers. Blood pressure and subjective drug effects also increased more rapidly in poor metabolizers. However, these differences are small because MDMA itself inhibits CYP2D6 activity.
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.
Frontiers in Pharmacology
July 13, 2022
Patrick Vizeli, Isabelle Straumann, Urs Duthaler et al.
43 citations
A single 125 mg dose of MDMA, given to 30 healthy men after fear conditioning and two hours before extinction learning, reduced skin conductance responses to a conditioned fear cue during both extinction learning and its recall the next day, compared with placebo. The drug did not affect fear-potentiated startle responses. Subjective feelings of trust and openness during extinction learning were linked to poorer discrimination between danger and safety cues during recall. MDMA raised oxytocin levels fourfold, but this increase did not correlate with fear extinction outcomes. The findings suggest MDMA can accelerate fear extinction learning and retention, at least for some physiological measures of fear, which may help explain its therapeutic benefit in PTSD.
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.
PLoS ONE
April 13, 2019
Patrick Vizeli, Matthias E Liechti
37 citations
MDMA increases oxytocin, empathy, and prosociality. In a pooled analysis of eight double-blind, placebo-controlled studies involving up to 132 healthy subjects, a specific genetic variant of the oxytocin receptor (rs1042778 TT genotype) was linked to greater feelings of trust after MDMA compared to G allele carriers, but only in a subset of 53 subjects. Other variants (rs53576 and rs2254298) did not moderate MDMA's subjective effects. MDMA increased plasma oxytocin concentrations, but oxytocin levels did not differ by gene variant. The results suggest oxytocin receptor variations may influence some prosocial effects of MDMA, but interpretation is cautious due to small sample sizes.
Metabolites
July 27, 2020
Andrea E. Steuer, Daria Kaelin, Martina I. Boxler et al.
32 citations
Three psychoactive stimulants—MDMA, amphetamine, and the new psychoactive substance mephedrone—alter blood metabolites in overlapping but distinct ways. Using plasma samples from controlled human administration studies and liquid chromatography-high resolution mass spectrometry, researchers identified changes in metabolites linked to energy metabolism, steroid biosynthesis, and amino acid pathways. Linoleic acid and pregnenolone-sulfate shifted similarly after intake of all three drugs. Mephedrone produced a metabolic profile more like amphetamine than MDMA, particularly in energy metabolism. These findings could guide future targeted studies on pharmacological actions and help identify biomarkers of drug use.
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.
Progress in neuro-psychopharmacology & biological psychiatry
January 10, 2024
Mesud Sarmanlu, Kim P C Kuypers, Patrick Vizeli et al.
17 citations
MDMA-assisted psychotherapy for PTSD shows promising safety and efficacy in clinical trials, but its underlying mechanisms are not well understood. This review examines preclinical and clinical evidence suggesting that MDMA's effects on memory processes—specifically fear extinction and fear reconsolidation—may contribute to the treatment's success. The authors integrate findings from cognitive psychology and psychopharmacology to support this view and provide recommendations for future research.
JAMA network open
November 4, 2024
Cihan Atila, Isabelle Straumann, Patrick Vizeli et al.
15 citations
A single dose of MDMA (ecstasy) caused acute hyponatremia (low blood sodium) in 31% of 96 healthy participants across four placebo-controlled trials. Hyponatremia occurred in 37% of those with unrestricted fluid intake but in none of the 15 participants whose fluid intake was restricted, suggesting fluid restriction may prevent this complication. The drop in sodium levels correlated with a sharp rise in oxytocin (433% increase) but not with copeptin, a marker of vasopressin. This challenges the long-held belief that MDMA-induced hyponatremia is caused by vasopressin release and instead points to oxytocin mimicking vasopressin's water-retaining effect in the kidneys due to structural similarity.
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.
European Journal of Clinical Pharmacology
December 2, 2017
Patrick Vizeli, Henriette E. Meyer zu Schwabedissen, Matthias E. Liechti
15 citations
Genetic variants of the norepinephrine transporter gene (SLC6A2) weakly influence the acute cardiovascular response to MDMA (ecstasy). In a pooled analysis of eight double-blind, placebo-controlled studies involving 124 healthy subjects, carriers of the GG genotype of the rs1861647 SNP showed higher increases in heart rate and rate-pressure product after MDMA than those with one or no G alleles. Subjects with a C allele in the rs2242446 SNP had greater heart rate elevations compared with the TT genotype. The AA genotype of the rs36029 SNP was associated with higher increases in mean arterial pressure and rate-pressure product than carriers of the G allele. Two other SNPs (rs168924 and rs47958) did not alter MDMA responses. These genetic factors may play a minor role in adverse cardiovascular events during recreational MDMA use.
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.
ACS Chemical Neuroscience
December 27, 2018
Patrick Vizeli, Henriette E. Meyer zu Schwabedissen, Matthias E. Liechti
13 citations
A pooled analysis of eight placebo-controlled studies in 124 healthy subjects tested whether common genetic variants in serotonin-system genes influence the physiological and subjective effects of 125 mg of MDMA. Variants in TPH2, HTR2A, and the serotonin-transporter gene showed only modest, non-significant associations after correction for multiple comparisons. No tested genetic polymorphism significantly altered the response to MDMA. The results suggest that interindividual differences in serotonin-system genes play a marginal role in MDMA's effects, whether used recreationally or therapeutically.
Frontiers in Psychiatry
October 24, 2019
Patrick Vizeli, Matthias E. Liechti
9 citations
MDMA (ecstasy), a recreational drug also studied as a treatment for PTSD, stimulates the dopamine system, which may contribute to its mood effects. Genetic differences in dopamine-related genes—including the D2 and D4 receptors and the dopamine transporter—were tested for their influence on subjective and autonomic responses to 125 mg of MDMA in 149 healthy volunteers across placebo-controlled crossover studies. After adjusting for multiple comparisons and individual differences in MDMA blood levels, none of the genetic variants significantly altered the drug's effects. Genetic variations in dopamine system genes are unlikely to explain why people respond differently to MDMA.