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 Proteome Research
June 27, 2018
Martina I. Boxler, Gabriel L. Streun, Matthias E. Liechti et al.
23 citations
A single 125 mg dose of MDMA alters dozens of endogenous metabolites in human plasma, including increases in cortisol, pregnenolone sulfate, and several inflammation mediators, alongside a decrease in calcitriol. These changes suggest heightened stress and serotonergic activity, activation of inflammatory pathways, and potential reduction in neuroprotective factors for brain dopamine neurons.
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.
Journal of Proteome Research
July 19, 2017
Martina I. Boxler, Matthias E. Liechti, Yasmin Schmid et al.
17 citations
A single dose of MDMA (ecstasy) alters the plasma metabolome in healthy adults. In a double-blind, placebo-controlled crossover trial with 15 participants, nine metabolites showed significant concentration changes after MDMA compared with placebo. The main changes involved glycerophospholipids, which may indicate increased energy production, and the ratio of methionine-sulfoxide to methionine, a potential marker of oxidative stress. Baseline samples were essential to avoid overestimating effects due to high interday variability among individuals.
Neuroscience Applied
January 1, 2025
Matthias E. Liechti, Peter Gasser, Helena Aicher et al.
16 citations
Switzerland's limited access program for psychedelic/MDMA-assisted therapy, started in 2014 with two physicians, had grown to about 100 physicians by 2024, treating 723 patients (245 with MDMA, 130 with LSD, 348 with psilocybin). Approximately 1660 treatments occurred in 2024, with patients typically receiving 2-4 sessions within 12 months. The program is authorized by the Swiss Federal Office of Public Health for patients with mostly incurable diseases where the substance can alleviate suffering and no alternatives exist or have failed. The article describes the program's history, legal requirements, costs, professional roles, education, patient characteristics, outcomes, and adverse effects, comparing it to similar programs in Canada and Australia.
European Neuropsychopharmacology
August 9, 2024
Friederike Holze, M. Madsen, Claus Svarer et al.
16 citations
Ketanserin, a drug that blocks the serotonin 2A (5-HT2A) receptor, occupies this receptor in the human brain in a dose-dependent manner. In a positron emission tomography (PET) study with healthy participants, oral doses of 10, 20, or 40 mg of ketanserin led to a plasma concentration-related increase in receptor occupancy. The half-maximal effective concentration (EC50) was 2.52 ng/mL, corresponding to about a 10 mg oral dose. These findings clarify how ketanserin works in the brain, aiding its use as a research tool and suggesting potential for treating bad psychedelic experiences.
Frontiers in Pharmacology
February 9, 2022
Karolina E. Kolaczynska, Dino Luethi, Dino Luethi et al.
16 citations
Mescaline, a psychedelic found in peyote, belongs to a class of compounds called scalines and 3C-scalines, which may serve as novel therapeutics for psychedelic-assisted therapy. This in vitro study examined several previously uninvestigated scalines and 3C-scalines at key monoamine targets. These compounds bound to the 5-HT2A receptor with weak to moderately high affinity (Ki = 150–12,000 nM). 3C-scalines showed a marginal preference for 5-HT2A over 5-HT2C and 5-HT1A receptors, while scalines showed no preference. Extending the 4-alkoxy substituent increased binding affinities and activation potency at 5-HT2A but not 5-HT2B receptors.
Clinical Pharmacology & Therapeutics
February 28, 2025
Lorenz Mueller, Alen Jelusic, Avram Tolev et al.
15 citations
In a double-blind, placebo-controlled crossover study with 23 healthy participants, daily paroxetine (an SSRI antidepressant) did not reduce the pleasant subjective effects of a single 100 μg dose of LSD, but it significantly lessened negative effects such as 'bad drug effect,' anxiety, and nausea. Paroxetine increased LSD's peak concentration and total exposure by 40% and 50%, respectively, by inhibiting the CYP2D6 enzyme, indicating this enzyme is involved in LSD metabolism. The interaction was strongest in normal CYP2D6 metabolizers and weakest in poor metabolizers. The findings suggest LSD can be safely added to SSRI treatment without dose adjustment when the SSRI inhibits CYP2D6, but no definitive recommendation can be made for other SSRIs.
Journal of Psychopharmacology
July 28, 2024
Kurt Stocker, Matthias E. Liechti
15 citations
MDMA is described by two terms—empathogen (promoting empathy and openness) and entactogen (promoting introspection and self-awareness). A review of the origin and usage of these terms finds no consistent reason why researchers choose one over the other. The authors argue that both properties stem from a single holistic experience: an intense feeling of connection. Entactogen refers to deep connection with oneself, empathogen to deep connection with others. They propose the new term connectogen to unify these effects, noting that MDMA may also foster connection with the here-and-now, the body, the world, and spiritual principles. The paper compares MDMA's connectogenic properties with those of classic psychedelics.
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.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
June 17, 2024
Hugo R. Arias, L. Micheli, Deborah Rudin et al.
14 citations
New non-hallucinogenic iboga alkaloid derivatives, called ibogalogs (TBG, IBG, and DM506), reduce pain hypersensitivity in mouse models of neuropathic and visceral pain. IBG provided the longest pain relief at a lower dose, while DM506 acted fastest. The pain-relieving effect was blocked by the 5-HT2A receptor antagonist ketanserin, indicating that activation of the 5-HT2A receptor, not its inhibition, mediates this activity. Ibogalogs activate 5-HT2A and 5-HT6 receptors and act as inverse agonists (except TBG) at the 5-HT7 receptor. Based on prior work, 5-HT6 inhibition and 5-HT7 activation relieve pain, so these receptors are not involved. The anti-hypersensitivity activity of ibogalogs in mice is mediated by 5-HT2A receptor activation.
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 Pharmacology
June 28, 2017
Patrick C. Dolder, Edna Grünblatt, Felix Müller et al.
12 citations
A single 100 μg dose of LSD did not change the expression of the serotonin 5-HT2A receptor gene (HTR2A) or the early growth response genes EGR1, EGR2, and EGR3 in the whole blood of 15 healthy subjects, measured 1.5 and 24 hours after administration. This null finding contrasts with rodent studies showing that LSD acutely increases EGR1 and EGR2 expression in the brain and that repeated use reduces 5-HT2A receptor binding. Whether chronic LSD administration alters gene expression in humans remains unknown.
Neurosci Appl
January 11, 2024
Drummond E-Wen McCulloch, Matthias E. Liechti, Kim PC. Kuypers et al.
10 citations
Psychedelic drugs like psilocybin and LSD are being tested in clinical trials for psychiatric and neurological conditions, with phase 2 studies showing particular promise for depression. At a 2023 European College of Neuropsychopharmacology meeting, experts identified key knowledge gaps that need addressing for successful medical implementation. These include understanding how these drugs work in the body (pharmacokinetics and pharmacodynamics), comparing different psychedelics, exploring the link between the duration of subjective effects and therapeutic outcomes, studying polypharmacology, and assessing the role of psychological support. The article also presents perspectives from the European Medicines Agency and Health Technology Assessors on what is most needed for medical adoption in Europe.
Psychedelic Medicine
January 20, 2025
Marianna Graziosi, Gabrielle Agin-Liebes, Mary P Cosimano et al.
9 citations
Psilocybin and other serotonergic psychedelics are used in research settings with safety measures including controlled environments, staff presence, screening, and psychoeducation. An analysis of study materials from psilocybin trials over the past two decades found that psychoeducation documents varied but commonly emphasized biological and physical safety, psychological safety and well-being, aspects of setting, and the potential for expectancies. The materials prioritized biological and psychological safety across all sites. The authors also identified elements unrelated to safety that may contribute to participant expectancies and suggest these extrapharmacological factors be studied systematically to maximize safety while minimizing extraneous expectancies.
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.
Nature Medicine
April 1, 2026
Manesh Girn, Manoj K. Doss, Leor Roseman et al.
8 citations
Psychedelic drugs are being studied again for their therapeutic potential, but how they change brain function is not well understood. By combining 11 brain-scanning datasets from five different psychedelics (psilocybin, LSD, mescaline, DMT, and ayahuasca) across three continents, researchers found a common pattern: increased communication between brain networks that handle high-level thinking (default, frontoparietal, and limbic) and those that handle sensory input (visual and somatomotor). Key deep-brain regions (thalamus, caudate, putamen) and the cerebellum also changed how they connect with sensorimotor networks. Contrary to some earlier studies, reductions in within-network connectivity were weak to moderate and varied by drug. These findings help resolve previous inconsistencies and provide a comprehensive map of how psychedelics alter large-scale brain organization.
Psychopharmacology
December 7, 2022
Adam L. Halberstadt, Dino Luethi, Marius C. Hoener et al.
7 citations
A series of 4-thio-substituted phenylalkylamines, including the psychedelic drugs 2C-T-2 and 2C-T-7, were tested in mice using the head twitch response (HTR), a behavioral proxy for human psychedelic effects. Adding an α-methyl group to the parent compound 2C-T increased potency fivefold, and extending the 4-methylthio group by one to three methylene units also increased potency. Fluorination of the 4-position alkylthio chain or a 4-allylthio substituent reduced activity, and bulky 4-benzylthio groups showed little or no effect. Binding studies confirmed nanomolar affinity for 5-HT2 receptor subtypes and partial agonism at 5-HT2A, supporting classification of these compounds as psychedelic drugs.
European Neuropsychopharmacology
April 1, 2022
Karolina E. Kolaczynska, Paula Ducret, Daniel Trachsel et al.
7 citations
MDA and related amphetamine-based compounds found in street drugs and sport supplements vary in their effects on monoamine transporters and receptors. Most compounds inhibited norepinephrine uptake most potently and preferentially blocked serotonin over dopamine uptake, except 3C-BOH and N,α-DEPEA, which favored dopamine uptake. Several compounds triggered monoamine release, and most bound to serotonin 5-HT2A and 5-HT2C receptors with micromolar affinity, acting as partial or full agonists at 5-HT2A and 5-HT2B. Some also interacted with adrenergic receptors and TAAR1. Fluorinated MDA analogs resembled MDMA's profile, while 3C-BOH and N,α-DEPEA showed amphetamine-like dopaminergic activity. Further pharmacokinetic and pharmacodynamic studies are needed to assess risks and therapeutic potential.
British Journal of Pharmacology
September 6, 2013
Cédric M. Hysek, Yasmin Schmid, Anna Rickli et al.
7 citations
A 125 mg dose of MDMA, a common recreational amount, produces only a moderate increase in body temperature in controlled clinical settings where risk factors like high ambient temperature, physical exertion, and dehydration are avoided. Severe hyperthermia, a rare but life-threatening complication of recreational MDMA use, typically requires additional permissive factors such as repeated or high doses, crowded conditions, or hyperthyroidism. The drug carvedilol, which blocks both α- and β-adrenoceptors, reduced MDMA-induced thermogenesis in humans and reversed established hyperthermia in rats, but its utility for treating severe MDMA toxicity in emergency settings remains unknown and requires further evaluation in case reports or series.
Current topics in behavioral neurosciences
July 31, 2024
Friederike Holze, Matthias E. Liechti, Felix Müller
4 citations
Psychedelics, including phenethylamines (e.g., mescaline), tryptamines (e.g., psilocybin), and ergolines (e.g., LSD), bind to the serotonin 5-HT2A receptor, causing profound alterations in sensation, cognition, emotions, and self-perception. While generally considered physiologically safe compared to other recreational drugs, they carry risks of lasting psychological adverse reactions such as persisting anxiety, dissociation, or flashbacks. This chapter provides a comprehensive overview of their pharmacology, origins, psychological and autonomic effects, interactions, risks, dosing, and consumption methods, distinguishing them from other psychoactive drugs like MDMA and ketamine based on distinct receptor profiles.
Neuroscience Applied
January 1, 2022
Friederike Holze, A. Becker, Karolina E. Kolaczynska et al.
3 citations
No Summary
5-HT2B Receptors
January 1, 2021
Dino Luethi, Matthias E. Liechti
3 citations
Stimulant and psychedelic drugs of abuse interact with monoaminergic systems, and the 5-HT_2B receptor is a relatively understudied target of serotonergic drugs. Activation of this receptor has been demonstrated for benzofuran-class stimulants and substituted amphetamines with a serotonergic profile, and may lead to cardiac valvulopathy. Many psychedelic drugs also activate the 5-HT_2B receptor, but the consequences remain unclear. Cardiac valvulopathy is likely not a concern with occasional psychedelic use, but may differ for microdosing regimens involving daily or multiple-times-weekly low doses.
European Neuropsychopharmacology
April 10, 2026
Deborah Rudin, Jan Valenta, Helene Rolli et al.
2 citations
Serotonergic psychedelics primarily activate the serotonin 2A receptor, but their full effects involve multiple receptor subtypes and signaling pathways. Using stable cell lines and bioassays measuring phospholipase C activation via inositol monophosphate formation, phospholipase A2 activation, β-arrestin2 recruitment, and Gαi-protein dissociation across 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT1A receptors, the study found that inositol monophosphate formation provides the most robust measure of 5-HT2 receptor activation and correlates strongly with known psychoactive doses. Most psychedelics showed signaling bias toward the PLC-IP1 or PLA2-AA pathway at the 5-HT2A receptor. The 5-HT2A/5-HT1A activation ratio may indicate seizure risk and therapeutic potential. Low activation at the 5-HT2B receptor suggests reduced cardiac risk with intermittent use, while strong 5-HT2C receptor activation aligns with low abuse potential.
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.