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.
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.
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.
International Journal of Molecular Sciences
July 31, 2021
Karolina E. Kolaczynska, Jan Thomann, Marius C. Hoener et al.
35 citations
Pyrovalerone cathinones, a class of potent psychoactive substances, were tested for their effects on monoamine transporters and receptors. All tested compounds strongly inhibited the dopamine and norepinephrine transporters, with IC50 values in the low micromolar range, but showed no activity at the serotonin transporter at concentrations below 10 µM. None of the substances triggered monoamine efflux. Two compounds, 4F-PBP and NEH, were particularly selective for the dopamine transporter, suggesting they likely produce strong psychostimulant effects and have high abuse potential. Extending the alkyl chain increased inhibition potency at dopamine and norepinephrine transporters, while a 3,4-methylenedioxy group enhanced serotonin transporter inhibition.
Frontiers in Pharmacology
April 24, 2019
Dino Luethi, Melanie Walter, Xun Zhou et al.
33 citations
Halogenated derivatives of amphetamine-type stimulants, such as 4-fluoroamphetamine and 4-chloroamphetamine, inhibit the norepinephrine transporter at submicromolar concentrations and the dopamine transporter at low micromolar concentrations. As the size of the para-substituent increases, selectivity shifts from dopamine to serotonin transporter inhibition, resulting in potent serotonin uptake inhibition. All tested compounds deplete cellular ATP at lower concentrations (0.25–2 mM) than they cause cell membrane integrity loss (≥0.5 mM), indicating mitochondrial toxicity. The toxicity rank order for para-substituents is chloride > fluoride > hydrogen. Para-halogenation increases the risk of serotonergic neurotoxicity and may heighten hepatic toxicity through mitochondrial impairment.
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.
Frontiers in Psychiatry
October 22, 2020
Felix Müller, Markus Mühlhauser, Friederike Holze et al.
31 citations
A woman with severe, treatment-resistant depression and a complex personality disorder received weekly, ascending doses of LSD in an open psychiatric ward. Despite adequate dosing confirmed by blood tests, she experienced no substantial acute subjective drug effects. However, she showed rapid and significant improvements in depressed mood, emotional instability, low energy, and suicidal thoughts. Questionnaire scores also decreased in global severity and various psychopathological subscales. Improvements lasted about 7 days after each dose. The case suggests that LSD can induce rapid but transient beneficial effects on several symptoms, and that these improvements can occur without acute drug experiences, resembling the time course of ketamine's antidepressant effects.
Journal of Clinical Laboratory Analysis
May 26, 2017
Patrick C. Dolder, Matthias E. Liechti, Katharina Rentsch
31 citations
A liquid chromatography tandem mass spectrometry method was developed and validated to measure lysergic acid diethylamide (LSD) and several of its metabolites in human plasma. After controlled administration of 100 μg LSD to 24 healthy subjects, the method accurately and precisely quantified LSD in all plasma samples, with a quantification limit of 0.05 ng/mL. Other compounds—iso-LSD, 2-oxo-3-hydroxy LSD, nor-LSD, lysergic acid monoethylamide, lysergic acid ethyl-2-hydroxyethylamide, 2-oxo-LSD, trioxylated-LSD, and 13/14-hydroxy-LSD—were only sporadically detected at levels too low for quantification.
International Journal of Molecular Sciences
April 18, 2020
Xun Zhou, Jamal Bouitbir, Matthias E. Liechti et al.
29 citations
Halogenating amphetamines and methcathinones at the para position increases their neurotoxic properties. In lab-grown SH-SY5Y cells, 4-fluoroamphetamine (4-FA), 4-chloroamphetamine (PCA), and 4-chloromethcathinone (4-CMC) reduced cellular energy (ATP) and damaged plasma membranes, with differentiated cells less sensitive than undifferentiated ones. The order of toxicity was chloride > fluoride > hydrogen for both drug families. These compounds also lowered mitochondrial membrane potential, disrupted the electron transport chain, raised reactive oxygen species, and triggered apoptosis via the intrinsic pathway. Although the toxic concentrations exceeded those needed for psychoactive effects, the findings raise concerns about uncontrolled recreational use of these designer drugs.
The International Journal of Neuropsychopharmacology
November 22, 2017
André Schmidt, Felix Müller, Patrick C. Dolder et al.
25 citations
Modafinil, but not methylphenidate or MDMA, increased brain activity in a limbic-cortical-striatal-pallidal-thalamic circuit and the amygdala when healthy subjects viewed fearful faces. Activation in frontal brain regions correlated with increased feelings of fearfulness and depressiveness after modafinil. Despite modafinil's cognitive enhancement effects, potential adverse effects on emotion processing should be considered.
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.
Frontiers in Pharmacology
November 28, 2019
Karolina E. Kolaczynska, Dino Luethi, Daniel Trachsel et al.
24 citations
A series of 4-alkyloxy-substituted 2,5-dimethoxyamphetamines and their phenethylamine congeners (2C-O derivatives) were tested for binding and activation at serotonin, adrenergic, dopamine, and trace amine receptors, as well as monoamine transporters. Both amphetamine and phenethylamine derivatives bound with moderate to high affinity to the 5-HT2A receptor, with preference over 5-HT1A and 5-HT2C receptors. Extending the 4-alkoxy group generally increased binding affinities at 5-HT2A and 5-HT2C receptors but had mixed effects on activation. Phenethylamines bound more strongly to TAAR1 than their amphetamine analogs. The authors suggest that, based on high 5-HT2A binding, some compounds may produce psychedelic-like effects in humans.
Neuropharmacology
June 23, 2018
Julian Maier, Felix P. Mayer, Dino Luethi et al.
24 citations
4,4′-DMAR, a new psychoactive substance linked to 31 deaths in Europe between June 2013 and February 2014, acts as a potent non-selective monoamine releasing agent. It inhibits dopamine, norepinephrine, and serotonin transporters at low micromolar concentrations (IC50 values below 2 μM) and induces reverse transport via these transporters. It also inhibits the vesicular monoamine transporter 2 in both rat and human cells with potency similar to MDMA. Unlike aminorex and 4-methylaminorex, 4,4′-DMAR strongly affects the serotonin transporter, suggesting fatalities may involve monoaminergic toxicity including serotonin syndrome. Its activity at VMAT2 indicates potential long-term neurotoxicity with chronic abuse.
Journal of Psychopharmacology
June 27, 2005
Franz X. Vollenweider, Matthias E. Liechti, Martin P. Paulus
24 citations
MDMA alters decision-making in a way that depends on the degree of success or failure. In a crossover trial with 42 healthy volunteers, a single 1.5 mg/kg oral dose of MDMA increased how much previous responses and stimuli influenced current choices, particularly when error rates were low (20% and 50%). The drug did not significantly change basic response characteristics like response latency or switching, and participants' self-assessed psychological states did not predict the decision-making patterns. These results suggest that acute MDMA affects success-related response selection during decision-making.