Psychopharmacology
May 27, 2017
Patrick C. Dolder, Felix Müller, Yasmin Schmid et al.
118 citations
At equally cardiostimulant doses, MDMA (125 mg) produced distinct subjective, emotional, sexual, and endocrine effects compared to methylphenidate (60 mg) and modafinil (600 mg) in healthy participants. MDMA increased pupil dilation, subjective good drug effects, drug liking, happiness, trust, well-being, and alterations in consciousness, while reducing anxiety and impairing fear recognition, leading to misclassifications of emotions as happy. It also induced sexual arousal-like effects and marked increases in cortisol, prolactin, and oxytocin. Methylphenidate increased anxiety and, along with modafinil, increased misclassifications of emotions as angry. Modafinil had no significant subjective effects but produced sympathomimetic and adverse effects.
Clinical Pharmacology & Therapeutics
December 12, 2022
Friederike Holze, Urs Duthaler, A. Becker et al.
116 citations
Psilocybin is being studied as a treatment for psychiatric and neurological disorders. After oral administration of 15, 25, or 30 mg to healthy subjects, peak psilocin concentrations averaged 11, 17, and 21 ng/mL, reached after about 2 hours, with elimination half-lives around 1.4–1.8 hours. Subjective effects lasted 5.5–6.4 hours, and maximal 'any drug' effects ranged from 58% to 80%. Psilocin showed dose-proportional pharmacokinetics, and both duration and intensity of effects were dose-dependent. Body weight did not influence pharmacokinetics or response.
British Journal of Pharmacology
March 13, 2015
Anna Rickli, Simone Kopf, Marius C. Hoener et al.
115 citations
Benzofurans, a class of newly used psychoactive substances, inhibit norepinephrine and serotonin uptake more than dopamine uptake, similar to MDMA and unlike methamphetamine. They also release monoamines and interact with trace amine-associated receptor 1, like classic amphetamines. Most benzofurans are partial 5-HT2A receptor agonists, similar to MDMA, but also activate 5-HT2B receptors, which is associated with heart valve fibrosis, unlike MDMA and methamphetamine. The benzodifuran 2C-B-FLY potently interacts with 5-HT2 receptors and binds to TA1 receptors, indicating predominant hallucinogenic properties and a risk for vasoconstriction.
The International Journal of Neuropsychopharmacology
June 24, 2015
Patrick C. Dolder, Yasmin Schmid, Manuel Haschke et al.
110 citations
Oral lysergic acid diethylamide (LSD) shows dose-proportional pharmacokinetics, with peak concentrations reached about 1.5 hours after ingestion and a terminal half-life of approximately 3.6 hours. The drug's effects are closely related to its blood concentration, with subjective effects lasting up to 12 hours. These findings provide a reference for clinical studies and for assessing LSD intoxication.
The International Journal of Neuropsychopharmacology
November 4, 2022
Aaron Klaiber, Friederike Holze, Ioanna Istampoulouoglou et al.
100 citations
Lysergic acid diethylamide (LSD) produces its acute psychedelic effects by stimulating the serotonin 5-HT2A receptor. In a double-blind, randomized, placebo-controlled, crossover study with 24 healthy participants, the 5-HT2A antagonist ketanserin (40 mg orally) was given one hour after LSD (100 µg orally). Ketanserin reversed the acute response to LSD, reducing the duration of subjective effects from 8.5 hours with placebo to 3.5 hours. It also reversed LSD-induced alterations of mind, including visual and acoustic alterations and ego dissolution, and reduced adverse cardiovascular effects and mydriasis. Ketanserin did not alter LSD's pharmacokinetics or its elevation of brain-derived neurotrophic factor levels. The findings indicate that LSD produces its psychedelic effects only when occupying 5-HT2A receptors, and ketanserin can shorten and attenuate the LSD experience for research and therapy.
Journal of Psychopharmacology
August 25, 2020
Johannes G. Ramaekers, Nadia R. P. W. Hutten, Natasha L. Mason et al.
95 citations
A low dose of LSD (20 micrograms) that does not cause a psychedelic experience can increase pain tolerance and reduce the unpleasantness of pain in healthy volunteers. In a controlled experiment with 24 participants, those given 20 µg of LSD kept their hand in cold (3°C) water longer and reported less pain than when given a placebo. Smaller doses (5 and 10 µg) did not produce the same effect. The 20 µg dose caused slight increases in blood pressure, anxiety, and dissociation, but no profound mind-altering effects. These findings suggest that very low doses of LSD may offer a new approach to pain management without the intense psychological effects of higher doses.
Journal of Psychoactive Drugs
June 1, 2002
Franz X. Vollenweider, Matthias E. Liechti, Alex Gamma et al.
92 citations
Since the mid 1990s, MDMA has been increasingly used recreationally as 'Ecstasy' by young people in Europe and the United States, yet systematic data on its psychological and neurobiological effects have been scarce. The authors conducted several studies in healthy human volunteers using placebo-controlled within-subject designs, standardized psychometric ratings, and neuropsychological tests to characterize the acute, short-term, and prolonged effects of MDMA. They also used specific receptor antagonists and Positron Emission Tomography to explore the neurotransmitter systems and functional neuroanatomy involved. This summary covers MDMA's acute effects on psychological and cognitive measures, information processing, and regional brain activity in healthy volunteers.
The Journal of Clinical Endocrinology & Metabolism
June 30, 2011
Linda D. Simmler, Cédric M. Hysek, Matthias E. Liechti
91 citations
MDMA (ecstasy) increases plasma copeptin, a marker for vasopressin secretion, in women but not in men. In a randomized placebo-controlled crossover trial with 16 healthy subjects, MDMA (125 mg) significantly elevated copeptin levels in women at 60 and 120 minutes, an effect prevented by pretreatment with duloxetine, which blocks MDMA-induced release of serotonin and norepinephrine. MDMA also tended to increase urine sodium and osmolality, indicating renal water retention, despite increased water intake. This sex difference in vasopressin secretion may explain why hyponatremia is more common in female ecstasy users.
Journal of Psychopharmacology
April 3, 2017
Kim P. C. Kuypers, Patrick C. Dolder, Johannes G. Ramaekers et al.
88 citations
A pooled analysis of six placebo-controlled studies with 118 participants confirmed that a single dose of MDMA (75 or 125 mg) increases emotional empathy—the ability to share and understand others' feelings—without affecting cognitive empathy, which involves recognizing others' emotions. The empathy boost was strongest for positive emotions and was linked to higher MDMA blood levels before testing. The effect was consistent across different labs and doses, and was not influenced by sex, prior drug use, or participants' baseline trait empathy. Although MDMA raised oxytocin levels, those increases did not explain the empathy changes.
Journal of Psychopharmacology
October 8, 2020
Yasmin Schmid, Peter Gasser, Peter Oehen et al.
82 citations
Lysergic acid diethylamide (LSD) and 3,4-methylenedioxymethamphetamine (MDMA) are being reinvestigated as treatments for psychiatric disorders. In Switzerland, a compassionate use program allowed 18 patients (12 women, 6 men, aged 29–77) with posttraumatic stress disorder and major depression to receive LSD (100–200 µg) or MDMA (100–175 mg) in group settings from 2014–2018. Drug-assisted sessions occurred about every 3.5 months after 3–10 psychotherapy sessions. LSD produced pronounced alterations of consciousness and mystical-type experiences, with effects largely comparable to those in patients or healthy subjects treated alone in research settings. The data may inform further controlled studies of substance-assisted psychotherapy.
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.
Neuroscience & Biobehavioral Reviews
December 30, 2015
Felix Mueller, Claudia Lenz, Markus Steiner et al.
68 citations
Moderate use of MDMA (ecstasy) shows no convincing evidence of structural or functional brain alterations in neuroimaging studies. A review of 19 studies, each involving subjects with fewer than 50 lifetime episodes or under 100 tablets consumed, found no significant harmful effects. However, the lack of results is linked to high methodological variability in dosages and co-consumption of other drugs, low study quality, and small sample sizes.
Frontiers in Pharmacology
July 13, 2021
Friederike Holze, Isidora Avedisian, Nimmy Varghese et al.
66 citations
Lysergic acid diethylamide (LSD) dose-dependently increased both implicit and explicit emotional empathy in 16 healthy subjects, with the highest 200 µg dose producing a significant effect compared with placebo. The 200 µg dose also moderately increased plasma oxytocin levels. Blocking the serotonin 5-HT2A receptor with ketanserin reduced the LSD-induced oxytocin release but did not reduce the increases in emotional empathy. These results indicate that LSD enhances empathy through mechanisms that may be partially independent of its primary action on 5-HT2A receptors, whereas the oxytocin release depends on 5-HT2A receptor stimulation and aligns with the psychedelic effect of LSD.
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.
Clinical Pharmacology & Therapeutics
September 25, 2020
Friederike Holze, Matthias E. Liechti, Nadia R. P. W. Hutten et al.
63 citations
Very low doses of LSD (5, 10, and 20 µg) were given to 23 healthy participants in a double-blind, placebo-controlled crossover trial. LSD concentrations in the blood increased in proportion to dose, with maximal levels reached after about 1.1 hours and an average elimination half-life of 2.7 hours. The 5 µg dose produced no significant subjective effects. The 10 µg dose significantly increased feelings of being under the influence and good drug effect, starting at 1.1 hours, peaking at 2.5 hours, and lasting until 5.1 hours. The 20 µg dose also increased bad drug effects. The threshold for psychotropic effects was 10 µg.
Psychological Medicine
October 2, 2017
André Schmidt, Felix Müller, Claudia Lenz et al.
62 citations
Activating the serotonin 2A receptor with LSD impairs the brain's ability to stop or inhibit responses, and this breakdown is linked to visual hallucinations. In a double-blind, placebo-controlled experiment with 18 healthy adults, LSD reduced brain activity in regions including the frontal and cingulate cortex, middle temporal gyrus, and cerebellum during a response-inhibition task. Parahippocampal activation related differently to performance under LSD versus placebo. Less activation in the left superior frontal gyrus during LSD exposure was associated with greater cognitive impairment and visual imagery. The findings suggest that 5-HT2A receptor activation disrupts hippocampal-prefrontal circuits, which may promote visual hallucinations.
October 29, 2005
Matthias E. Liechti, Isabelle Kunz, Hugo Kupferschmidt
58 citations
Ecstasy (MDMA) toxicity often involves multiple substances, complicating the clinical picture. Among 52 patients presenting to an emergency department, most had also consumed alcohol (51.9%) or other illicit drugs (71.1%). Common reasons for seeking care were collapse or loss of consciousness (36.5%), palpitations (19.2%), dizziness or weakness (15.4%), and anxiety (13.5%). Co-use of cocaine was linked to panic reactions (30.7% vs. 7.7% without cocaine). Deep coma occurred in 68.8% of patients who also used GHB or opiates, but in none who took Ecstasy alone. Severe complications included cardiac arrest, hyperthermia, rhabdomyolysis, and one death.
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.