British Journal of Clinical Pharmacology
December 11, 2015
Matthias E. Liechti, Boris B. Quednow, Evangelia Liakoni et al.
57 citations
Gamma-hydroxybutyrate (GHB) produced mixed stimulant-sedative effects in healthy men, with higher doses causing more sedation and dizziness but no changes in heart rate or blood pressure. Plasma exposure to GHB rose disproportionately with dose—a 40% greater increase than expected from dose alone—indicating nonlinear pharmacokinetics. The psychotropic effects were closely tied to plasma concentrations, and no acute tolerance developed over time.
Journal of Clinical Psychopharmacology
July 13, 2013
Cédric M. Hysek, Anja E. Fink, Linda D. Simmler et al.
57 citations
Blocking α₁-noradrenergic receptors with the drug doxazosin reduces MDMA-induced increases in blood pressure and body temperature, and moderately lessens positive mood, but enhances rapid heart rate. In a randomized, double-blind, placebo-controlled crossover study with 16 healthy participants, doxazosin (8 mg daily for 3 days before MDMA 125 mg) altered several acute effects of MDMA. The findings suggest that α₁-adrenergic receptors play a role in the cardiovascular stimulant effects of MDMA and, to a minor extent, its thermogenic and euphoric effects in humans.
Journal of Chromatography B
December 7, 2020
Karolina E. Kolaczynska, Matthias E. Liechti, Urs Duthaler
55 citations
A rapid LC-MS/MS method was developed and validated to quantify psilocin, the active metabolite of psilocybin, and its metabolite 4-hydroxyindole-3-acetic acid (4-HIAA) in human plasma. Plasma samples were processed by protein precipitation with methanol. The method achieved inter-assay accuracy of 100-109% and precision ≤8.7%, with recovery ≥94.7% and consistent across concentration levels and plasma batches (CV% ≤4.1%). Plasma matrix caused negligible ion suppression, and endogenous interferences were separated. Samples could undergo three freeze-thaw cycles, remain at room temperature for 8 hours, or be stored at -20°C for 1 month without degradation (≤10%). The linear range (R ≥ 0.998) covered concentrations observed after a 25 mg oral dose of psilocybin, enabling pharmacokinetic assessment.
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.
Neuroscience & Biobehavioral Reviews
November 12, 2018
Felix Müller, Raphael Brändle, Matthias E. Liechti et al.
52 citations
A meta-analysis of neuroimaging studies found that people who use MDMA (ecstasy) have significantly lower serotonin transporter (SERT) density in eight out of thirteen brain regions examined, compared to non-users. The reduction in SERT density was positively associated with the duration of abstinence, suggesting that these brain changes may be partially reversible with sustained abstinence. No significant differences were found between users and controls in neurochemical ratios in the frontal and occipital lobes or in blood flow in the basal ganglia. The analysis included 356 MDMA users and 311 controls from sixteen studies, but the user groups showed heavy use patterns and the overall study quality was poor.
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.
Neuroendocrinology
January 1, 2014
Julia Seibert, Cédric M. Hysek, Carlos A. Penno et al.
52 citations
MDMA (ecstasy) but not methylphenidate (Ritalin) acutely alters several steroid hormones over 24 hours. In 16 healthy adults given single doses of MDMA (125 mg), methylphenidate (60 mg), both drugs together, or placebo on separate days, MDMA raised cortisol, corticosterone, 11-dehydrocorticosterone, and 11-deoxycorticosterone, and tended to increase aldosterone, while leaving cortisone, DHEA, DHEAS, androstenedione, and testosterone unchanged. Methylphenidate alone did not affect any steroid levels and did not modify MDMA's effects. These results indicate that serotonin release, not dopamine or norepinephrine stimulation, drives acute activation of the hypothalamic-pituitary-adrenal axis by these drugs.
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.
Biological Psychiatry Cognitive Neuroscience and Neuroimaging
February 1, 2024
Friederike Holze, Nirmal Singh, Matthias E. Liechti et al.
50 citations
Psychedelic compounds such as psilocybin, LSD, DMT, 5-MeO-DMT, and mescaline, all serotonin 2A receptor agonists, are under investigation as potential treatments. This review summarizes current clinical research on these five compounds, covering mechanisms of action, pharmacokinetics, pharmacodynamics, efficacy, and safety. Evidence for therapeutic indications remains scarce except for psilocybin for depression. No differences in psychedelic effects were noted beyond effect duration, and it is unclear whether different receptor profiles contribute to therapeutic potential. More research is needed to differentiate these compounds for various therapeutic uses.
Neuropharmacology
May 15, 2018
Dino Luethi, Daniel Trachsel, Marius C. Hoener et al.
50 citations
4-Thio-substituted phenethylamines (2C-T drugs) are potent psychedelics with poorly defined pharmacological properties. The study characterized their interactions with monoamine receptors and transporters. 2C-T drugs showed high affinity for 5-HT2A and 5-HT2C receptors (1-54 nM and 40-350 nM, respectively) and acted as potent partial agonists at 5-HT2A and 5-HT2B receptors, except benzylthiophenethylamines which did not potently activate 5-HT2B (EC50 > 3000 nM). They also bound to 5-HT1A and adrenergic receptors and interacted with rat but not human TAAR1, but did not potently affect monoamine transporters (Ki > 4000 nM). The receptor binding profile predicts psychedelic effects mediated by potent 5-HT2 receptor interactions.
Emergency Medicine Journal
April 8, 2010
C.m. Hysek, Franz X. Vollenweider, Matthias E. Liechti
50 citations
Beta-blockers may prevent MDMA-induced increases in heart rate but do not prevent hypertensive effects or other adverse effects of MDMA.
Experimental Neurology
June 4, 2021
Deborah Rudin, Matthias E. Liechti, Dino Luethi
48 citations
New psychoactive stimulants and psychedelics affect monoaminergic systems through different mechanisms: stimulants interact with monoamine transporters, while psychedelics act mainly as agonists at serotonin 5-HT2A receptors. Both types have been linked to neurological and cognitive impairments. In vitro and rodent studies suggest mechanisms such as cytotoxicity, mitochondrial dysfunction, and oxidative stress may contribute to neurotoxicity from stimulants, and serotonin 5-HT2A receptor-mediated toxicity and apoptosis pathways may contribute to neurotoxicity from psychedelics. It remains unclear how well these preclinical findings translate to humans.
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.
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.
European Journal of Pharmacology
December 8, 2017
Dino Luethi, Marius C. Hoener, Matthias E. Liechti
41 citations
Diclofensine, diphenidine, and methoxphenidine are new psychoactive substances that appeared on the illicit drug market. Diclofensine potently inhibited all three monoamine transporters (norepinephrine, dopamine, and serotonin) with similar inhibition potential in the range of 2.5-4.8 μM and also bound to adrenergic, dopamine, serotonin, and trace amine-associated receptors. Diphenidine inhibited norepinephrine and dopamine transporters in the low micromolar range but was a very weak serotonin transporter inhibitor, and it bound to adrenergic α1A and α2A receptors and serotonin 5-HT1A and 5-HT2A receptors. Methoxphenidine showed considerable inhibition only for the norepinephrine transporter and bound to adrenergic α2A and serotonin 5-HT2A and 5-HT2C receptors. None of the drugs mediated substrate-type efflux of monoamines. These interactions likely mediate the psychoactive effects of diclofensine and may contribute to those of diphenidine and methoxphenidine.
The International Journal of Neuropsychopharmacology
May 16, 2017
André Schmidt, Felix Müller, Patrick C. Dolder et al.
41 citations
Methylphenidate and modafinil, but not MDMA (ecstasy), improved the ability to stop a motor response in healthy adults. Using brain imaging, methylphenidate broadly activated frontal, temporal, and parietal regions, including the anterior cingulate cortex and presupplementary motor area, more than modafinil did. Modafinil increased activation in the right middle frontal gyrus and parietal lobule, while MDMA activated the right middle/inferior frontal gyrus and superior parietal lobule without improving performance. The findings suggest that methylphenidate may be superior to modafinil and MDMA for enhancing cognitive performance related to response inhibition in healthy people.
Drug Testing and Analysis
July 16, 2016
Andrea E. Steuer, Michael Poetzsch, Lorena Stock et al.
41 citations
A new microflow liquid chromatography tandem mass spectrometry method was developed to quantify LSD and its metabolites in human plasma, enabling detection limits of 0.01 ng/mL and separation within three minutes. In a controlled pharmacokinetic study, elimination half-lives of iso-LSD (median 12 h) and LSD metabolites (median 9, 7.4, 12, and 11 h for oxo-HO-LSD, HO-LSD, HO-LSD-gluc, and nor-LSD, respectively) exceeded that of LSD (median 4.2 h). However, screening for these metabolites to extend detection windows in plasma is not constructive because their concentrations are very low.
Journal of Psychopharmacology
April 30, 2019
Dino Luethi, Karolina E. Kolaczynska, Melanie Walter et al.
39 citations
Metabolites of the popular illicit drugs MDMA, methylone, and MDPV can interact with human monoamine transporters and receptors at concentrations relevant to their pharmacological effects. MDMA and methylone inhibited norepinephrine uptake more potently than dopamine or serotonin uptake. N-demethylation of MDMA did not change its uptake inhibition profile, but N-demethylation of methylone reduced overall potency. Opening the methylenedioxy ring produced catechol metabolites that maintained norepinephrine and dopamine uptake inhibition but had much weaker effects on serotonin uptake. Further O-methylation of these catechols reduced norepinephrine uptake inhibition, yielding metabolites without significant stimulant properties. N-demethylated metabolites of MDMA and methylone circulate unconjugated and may contribute to the drugs' effects in human users.
European Neuropsychopharmacology
December 4, 2014
Yasmin Schmid, Cédric M. Hysek, Katrin H. Preller et al.
39 citations
In a double-blind, placebo-controlled crossover study with 30 healthy adults, a single 40 mg dose of methylphenidate increased subjective ratings of sexual arousal when viewing explicit erotic pictures and led participants to press a button to prolong viewing of implicit sexual stimuli, whereas a 75 mg dose of MDMA did not alter sexual arousal. Neither drug changed how participants appraised the romantic relationships of unknown couples. Blood levels of testosterone, estrogen, and progesterone were unrelated to arousal ratings. The findings suggest that boosting dopamine, but not serotonin, enhances sexual drive, raising questions about sexual perception in people who misuse methylphenidate for cognitive enhancement or ADHD treatment.
Medicine
January 31, 2018
Evangelia Liakoni, Chris Yates, Alison M. Dines et al.
38 citations
Self-reported substance use by patients arriving at emergency departments with acute recreational drug toxicity matches toxicological analysis best for heroin (86.1% agreement) and cocaine (74.1% agreement). Inhalants, poppers, and magic mushrooms were self-reported but never detected analytically. Immunoassays accurately identified methadone (100% agreement) and cocaine (95.5% agreement) but were less consistent for amphetamines (81.8% agreement). Mass spectrometry confirmed MDMA, amphetamine, methamphetamine, and new psychoactive substances in many cases where immunoassays were negative, and revealed multiple-substance use. Diagnosis of new psychoactive substance use relied primarily on self-report.
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.