Journal of Psychopharmacology
September 20, 2024
Abigail E. Calder, Benjamin Rausch, Matthias E. Liechti et al.
17 citations
In Switzerland, where psychedelic-assisted therapy (PAT) is permitted under a limited medical use program, patients receiving PAT and healthy volunteers given LSD or psilocybin reported similar overall drug effects and mystical experiences. However, patients reported lower ratings of ego dissolution. Depressive symptoms, measured by the Montgomery-Åsberg Depression Rating Scale, significantly decreased in patients. The strongest predictor of antidepressant improvement was relaxation during the session, while mystical-type experiences did not predict antidepressant effects. Most patients had mild adverse effects that resolved within 48 hours. Hourly assessments of drug effects may better predict clinical outcomes than retrospective measures of mystical experience.
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.
Translational Psychiatry
July 15, 2024
Nadia R. P. W. Hutten, Conny W E M Quaedflieg, Natasha L. Mason et al.
16 citations
Repeated low doses of LSD (15 mcg) affect arousal, attention, and memory depending on a person's baseline cognitive state. In a randomized placebo-controlled trial with 53 healthy participants, LSD reduced resting-state EEG delta, theta, and alpha power (indicating stimulation) and enhanced pre-attentive processing during acute dosing sessions. LSD also blunted visual long-term potentiation (a marker of perceptual learning and memory) by the fourth dosing session. Stimulatory effects were strongest in individuals with low baseline arousal and attention, while inhibitory effects on memory were strongest in those with high baseline memory performance. Some EEG changes persisted at a one-week follow-up, suggesting possible neuroadaptations from repeated low-dose LSD.
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.
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.
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.
JAMA Psychiatry
June 1, 2025
Lorenz Mueller, Joyce Santos de Jesus, Yasmin Schmid et al.
14 citations
Repeated low doses of LSD (20 μg twice weekly for six weeks) did not reduce ADHD symptoms more than placebo in adults with moderate-to-severe ADHD. In a double-blind randomized trial with 53 participants, the LSD group showed an average 7.1-point improvement on the ADHD symptom scale, while the placebo group improved by 8.9 points—a difference that was not statistically significant. The treatment was physically safe and psychologically well tolerated. The findings suggest that microdosing LSD, despite popular interest, offers no advantage over placebo for ADHD symptom relief.
Neuropsychopharmacology
December 19, 2024
Livio Erne, Severin B Vogt, Lorenz Müller et al.
14 citations
Continuous intravenous infusions of DMT produce dose-dependent subjective effects that plateau after 30 minutes, with a ceiling effect for good drug effect at 1.8 mg/min. The highest dose tested (2.4 mg/min) caused greater anxious ego dissolution and significant anxiety compared to placebo. DMT showed dose-proportional pharmacokinetics and moderate acute tolerance. When participants could self-titrate their dose, they chose moderate to strong psychedelic effects comparable to the 1.8 mg/min rate. These findings can guide dose selection in future DMT research and show that subjective effects can be rapidly adjusted through dose titration.
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.
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.
European Journal of Pharmacology
March 5, 2024
Hugo R Arias, Deborah Rudin, Dustin J Hines et al.
12 citations
A non-hallucinogenic compound derived from ibogamine, DM506, produces anxiolytic- and sedative-like effects in mice without causing hallucinogenic head-twitch responses. At 15 mg/kg, DM506 induces both acute and long-lasting anxiety-reducing behavior in naive and stressed mice. Repeated 5 mg/kg doses show no cumulative effects or side effects. Higher doses (40 mg/kg) cause sedation that is blocked by the 5-HT2A receptor antagonist volinanserin. DM506 binds to human 5-HT2A (Ki = 24 nM) and 5-HT2B (Ki = 16 nM) receptors, activating them with EC50 values of 9 nM and 3 nM, respectively, acting as a partial agonist compared to the full agonist DOI. Electroencephalography shows increased transition from alert to deep-sleep brain wave activity.
British Journal of Clinical Pharmacology
January 1, 2024
Friederike Holze, Livio Erne, Urs Duthaler et al.
12 citations
After oral doses of 85 and 170 μg, LSD reaches peak blood concentrations of 1.8 and 3.4 ng/mL at about 1.7 hours, with elimination half-lives of 3.7 and 4.0 hours. Only 1% of the dose is excreted unchanged in urine within 24 hours, while 16% is eliminated as the metabolite 2-oxo-3-hydroxy-LSD. Subjective drug effects last 9.3 to 11 hours, with maximal intensity reaching 77% to 87%. LSD shows dose-proportional pharmacokinetics and first-order elimination, and its effects are dose-dependent. The findings confirm earlier work on LSD's metabolism and time course.
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.
European Journal of Endocrinology
March 27, 2025
Cihan Atila, Andi Nikaj, Svenja Leibnitz et al.
9 citations
Neurophysin I (NP-I), a stable byproduct of the oxytocin precursor, can serve as a reliable biomarker for oxytocin secretion when stimulated by MDMA. In a double-blind, placebo-controlled crossover study, 15 patients with hypothalamic-posterior-pituitary dysfunction and 15 matched healthy controls received a single 100 mg dose of MDMA or placebo. In healthy controls, MDMA caused an 8-fold increase in oxytocin (peak: 624 pM) and a 20-fold increase in NP-I (peak: 1508 pM). Patients showed no notable oxytocin increase (peak: 92 pM) and only a mild NP-I rise (peak: 263 pM). The difference in NP-I area under the curve between groups was significant (2340 pM·5 h; 95% CI, 1462-3218). NP-I measurement offers a way to assess oxytocin secretion, aiding research into conditions like autism, anxiety, and depression.
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
January 1, 2023
Deborah Rudin, Alexander Areesanan, Matthias E. Liechti et al.
9 citations
Classic psychedelics LSD, psilocin, DMT, and mescaline do not directly alter the proliferation or cytokine release of primary human T lymphocytes, nor do they stimulate NF-κB induction in monocytes. These findings indicate no relevant direct immune-modulatory effects of these substances on the tested human immune cells in vitro. The results support the safety of using classic psychedelics in assisted psychotherapy for patients with life-threatening conditions where immune suppression would be harmful.
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.