Biological psychiatry
February 1, 2023
Friederike Holze, Peter Gasser, Felix Müller et al.
294 citations
LSD-assisted therapy produced long-lasting reductions in anxiety and comorbid depression symptoms up to 16 weeks in patients with anxiety related to a life-threatening illness. In a double-blind, placebo-controlled crossover trial with 42 patients, LSD treatment led to significant decreases in anxiety scores compared to placebo, with a large effect size. Similar improvements were seen in depression ratings. Positive acute subjective drug effects and mystical-type experiences correlated with long-term anxiety reductions. Mild, transient side effects occurred in 19% of patients, and one serious adverse event (acute transient anxiety) was reported.
Neuropsychopharmacology
April 27, 2017
Matthias E Liechti
230 citations
Over the past 25 years, six clinical studies have examined the classic hallucinogen LSD in healthy subjects and patients. In controlled settings, LSD acutely produces bliss, audiovisual synesthesia, altered meaning of perceptions, derealization, depersonalization, and mystical experiences, mediated by the 5-HT2A receptor. It increases feelings of closeness, openness, trust, and suggestibility, impairs recognition of sad and fearful faces, reduces left amygdala reactivity to fearful faces, enhances emotional empathy, and increases emotional response to music. LSD also causes sensorimotor gating deficits, weak autonomic stimulation, and elevated cortisol, prolactin, and oxytocin.
Neuropharmacology
December 1, 2015
Anna Rickli, Dino Luethi, Julian Reinisch et al.
216 citations
NBOMe drugs, a class of novel psychoactive substances, bind strongly to serotonin receptors (5-HT2A, 5-HT2B, 5-HT2C) and rat trace amine-associated receptor-1, with most affinities and potencies below 1 μM, similar to LSD. Unlike LSD, NBOMe drugs also interact with α1 receptors, suggesting they may produce hallucinogenic effects comparable to LSD but with additional stimulant properties. The study characterized the receptor binding profiles of twelve 2C drugs, their NBOMe analogs, and LSD in human cells expressing human receptors or transporters, except for TAAR1 where rat/mouse receptors were used.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
October 1, 2023
Laura Ley, Friederike Holze, Denis Arikci et al.
127 citations
At equally strong doses, the classic psychedelics mescaline, LSD, and psilocybin produce comparable subjective experiences, with no evidence of qualitative differences in altered states of consciousness. Autonomic effects were moderate; psilocybin increased diastolic blood pressure more than LSD, while LSD showed a trend toward higher heart rate than psilocybin. Mescaline had the longest effect duration (mean 11.1 hours), followed by LSD (8.2 hours) and psilocybin (4.9 hours). Mescaline and LSD, but not psilocybin, raised circulating oxytocin. None altered brain-derived neurotrophic factor. Tolerability was similar, though mescaline caused slightly more subacute adverse effects 12–24 hours later.
Translational psychiatry
May 23, 2023
Severin B Vogt, Laura Ley, Livio Erne et al.
85 citations
Intravenous DMT can produce a psychedelic state that is short-lasting and controllable. A double-blind, placebo-controlled crossover trial with 27 healthy participants tested five DMT regimens: low infusion (0.6 mg/min), high infusion (1 mg/min), low bolus plus low infusion (15 mg + 0.6 mg/min), and high bolus plus high infusion (25 mg + 1 mg/min). Bolus doses induced very intense effects within 2 minutes, with more negative feelings and anxiety than infusions. Infusions produced slowly increasing, dose-dependent effects that plateaued after 30 minutes. All effects subsided within 15 minutes of stopping the infusion. Acute tolerance developed, with stable subjective effects from 30 to 90 minutes despite rising plasma concentrations. Intravenous DMT infusion is a promising tool for tailored psychedelic therapy.
Temperature
October 31, 2014
Matthias E Liechti
64 citations
MDMA (Ecstasy) causes a dose-dependent rise in core body temperature of 0.2–0.8°C in healthy subjects under controlled conditions, but moderately hyperthermic temperatures above 38.0°C occur frequently at higher doses even without physical activity. The hyperthermia results from MDMA releasing norepinephrine, which increases metabolic heat generation and causes cutaneous vasoconstriction that impairs heat dissipation. The role of serotonin is unclear. Severe hyperthermia is managed with sedation, intravenous fluids, cooling, and mechanical ventilation.
Psychopharmacology
September 13, 2021
Friederike Holze, Toya V Caluori, Patrick Vizeli et al.
57 citations
LSD dose-dependently increased subjective, physiologic, and adverse effects in healthy subjects. Positive subjective effects (good drug effect) were more pronounced than negative ones (bad drug effect), with maximal ratings of >50% good drug effects reached in 37%, 91%, 96%, and 91% of administrations at 25, 50, 100, and 200 µg, respectively, versus 0%, 9%, 27%, and 31% for bad drug effects. Physiologic effects were moderate: no systolic blood pressure exceeded 180 mmHg, peak heart rate >100 beats/min occurred in up to 25% of subjects at the highest dose, and peak body temperature >38°C in up to 34%. Kidney and liver function remained unaltered. Six subjects reported transient flashbacks. Single-dose LSD is safe regarding acute psychological and physical harm in healthy subjects in a controlled research setting.
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.
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.
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.
Current topics in behavioral neurosciences
January 1, 2022
Matthias E Liechti, Friederike Holze
35 citations
Proper dosing is crucial for the clinical use of classic psychedelics and entactogens, which are being studied for psychiatric conditions such as anxiety, depression, cluster headache, and posttraumatic stress disorder. Controlled study data on dosing with well-characterized pharmaceutical formulations are scarce. The dose equivalence of different substances, dose-response effects, and subjective effects at various doses are important for their use in psychotherapy. Microdosing has gained popularity, and the first placebo-controlled studies of LSD have been published. This chapter covers pharmaceutical aspects, definitions of different doses including microdoses, personalized dosing, and non-pharmacological factors that influence response.
The British journal of psychiatry : the journal of mental science
September 1, 2024
Friederike Holze, Peter Gasser, Felix Müller et al.
32 citations
A long-term follow-up of a double-blind, placebo-controlled crossover trial found that LSD-assisted therapy produced sustained reductions in anxiety and depression for up to 94 weeks after the last treatment. Participants who received LSD first showed a decrease of 21.6 points on the State-Trait Anxiety Inventory, and those who received LSD second showed a decrease of 16.5 points, both statistically significant. Comorbid depression also improved, with Beck Depression Inventory scores dropping by 8.1 and 8.9 points in the two groups. Personality traits shifted toward lower neuroticism and higher extraversion. Patients attributed lasting positive effects to the psychedelic experience.
Progress in brain research
January 1, 2018
Felix Müller, Matthias E Liechti, Undine E Lang et al.
32 citations
Studies of hallucinogenic drugs on the resting brain show some consistent findings: psilocybin, LSD, and ayahuasca all decrease cerebral blood flow and increase global functional connectivity in the precuneus and thalamus. LSD also consistently reduces functional connectivity within distinct resting state networks. However, results for connectivity between networks and blood flow in other brain regions show little convergence. These studies are limited by small sample sizes and potential bias from unspecific drug effects on physiology and the vascular system. Current evidence suggests neuroimaging may help reveal the neural correlates of hallucinogenic effects.
Translational psychiatry
September 30, 2024
Aaron Klaiber, Yasmin Schmid, Anna M Becker et al.
27 citations
Mescaline produces dose-dependent subjective and physiological effects in healthy people, with doses above 100 mg increasing blood pressure and heart rate. Subjective effects lasted from 6.4 hours at 100 mg to 14 hours at 800 mg, and the drug reached peak concentration in blood after about 2 hours with a half-life of 3.5 hours. Nausea and vomiting were common at the highest dose. Blocking serotonin 5-HT2A receptors with ketanserin reduced the effects of 800 mg mescaline to levels similar to lower doses, indicating that mescaline's acute effects are primarily mediated by these receptors.
Molecular psychiatry
April 1, 2025
Mihai Avram, Lydia Fortea, Lea Wollner et al.
26 citations
Lysergic acid diethylamide (LSD), d-amphetamine, and MDMA each reduce the integrity (within-network connectivity) of several brain networks, with LSD uniquely reducing integrity in the default-mode network. Contrary to expectations, amphetamines reduced integrity in more networks than LSD. LSD produced more pronounced decreases in between-network segregation, while amphetamines also induced increases. Seed-based connectivity mostly increased between networks across all substances, with LSD showing stronger effects than both amphetamines. All substances decreased global connectivity in visual areas, but LSD specifically increased global connectivity in the basal ganglia and thalamus. These findings clarify distinctive neurobiological effects of psychedelics and support further investigation of their therapeutic potential.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
December 15, 2022
Dino Luethi, Karolina E Kolaczynska, Severin B Vogt et al.
24 citations
A new LC-MS/MS method accurately measures the psychedelic compound DMT and its major metabolites IAA and DMT-NO in human plasma. The assay uses a simple protein precipitation step, a pentafluorophenyl column for separation, and detects analytes via mass spectrometry. Calibration ranges cover 0.25–250 ng/mL for DMT, 0.1–100 ng/mL for DMT-NO, and 25–25,000 ng/mL for IAA (using a labeled internal standard to account for endogenous IAA). Accuracy ranged from 93% to 113% with precision ≤11%. The method successfully determined pharmacokinetic parameters in participants receiving a 90-minute intravenous infusion of 1 mg/min DMT. It is easy to use, has a short run time, and is suitable for clinical DMT pharmacokinetic and metabolism studies.
BMC pharmacology & toxicology
May 26, 2016
Evangelia Liakoni, Patrick C Dolder, Katharina M Rentsch et al.
24 citations
Of 50,624 emergency department visits at a Swiss university hospital over one year, 210 were due to acute recreational drug toxicity. Patients averaged 33 years old, 73% were male. Cocaine (33%), cannabis (32%), and heroin (14%) were the most reported substances; analytical testing confirmed cannabis (33%), cocaine (27%), and opioids excluding methadone (19%) most often. Only two cases involved novel psychoactive substances (NPS): one severe intoxication with PMMA and one minor with 2C-P. Common symptoms included tachycardia (28%), anxiety (23%), nausea or vomiting (18%), and agitation (17%). Severe outcomes included two deaths, two heart attacks, 13 seizures, and six psychosis cases. Most patients (76%) were discharged; 10% required intensive care. Classic drugs like cocaine and cannabis caused most problems, while NPS were rarely seen despite their increased detection elsewhere.
Med (New York, N.Y.)
June 4, 2025
Felix Müller, Hannes Zaczek, Anna M Becker et al.
21 citations
In a double-blind, low-dose controlled trial, 61 patients with moderate-to-severe major depressive disorder received supportive psychotherapy and either two high doses (100 μg then 200 μg) or two low doses (25 μg each) of LSD. At the primary endpoint two weeks after the second session, the high-dose group showed a greater average reduction in self-rated depression scores (11.8 points) compared to the low-dose group (3.9 points), a difference that approached but did not reach statistical significance. Clinician-rated scores also favored the high dose, but significance was lost after adjusting for baseline depression severity. Improvements were numerically maintained through 12 weeks. Adverse events were similar between groups. The authors suggest these exploratory results warrant a larger phase 3 trial.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
December 1, 2024
Isabelle Straumann, Isidora Avedisian, Aaron Klaiber et al.
20 citations
The two mirror-image forms of MDMA, S-MDMA and R-MDMA, produce different acute effects in humans. S-MDMA (125 mg) caused stronger feelings of stimulation, happiness, and openness, and larger increases in blood pressure than R-MDMA (125 or 250 mg) or racemic MDMA (125 mg). R-MDMA did not produce more psychedelic-like effects than S-MDMA. S-MDMA also increased plasma prolactin, cortisol, and oxytocin more than the other forms. The body eliminated S-MDMA faster (half-life 4.1 hours) than R-MDMA (half-life 12-14 hours). The findings suggest that S-MDMA's stronger stimulant effects are due to its higher potency rather than a qualitative difference, and that equivalent effects may occur at doses of 100 mg S-MDMA, 125 mg racemic MDMA, and 300 mg R-MDMA.
Journal of analytical toxicology
January 1, 2017
Adrian Stoller, Patrick C Dolder, Michael Bodmer et al.
19 citations
A 19-year-old male was admitted to the emergency department with severe hallucinations, dilated pupils, rapid heart rate, agitation, and confusion after using a substance sold as 2C-B. Laboratory analysis using liquid chromatography-mass spectrometry detected the more potent synthetic phenethylamine derivative 2C-P instead. Based on two blood samples, the estimated elimination half-life was 19 hours. The case illustrates how small structural variations in the 4 position of the phenyl ring, such as a propyl group in 2C-P versus bromine in 2C-B, can lead to significant differences in drug potency and duration of action, contributing to adverse effects.
PLoS ONE
June 15, 2016
Andrea E Steuer, Corina Schmidhauser, Eva H Tingelhoff et al.
18 citations
Bupropion pretreatment increased the maximum plasma concentration and overall exposure of both MDMA stereoisomers, while reducing the levels of its major metabolites by about 40%, in healthy volunteers. These changes in MDMA pharmacokinetics due to reduced CYP2D6 activity were similar to those seen in people with naturally lower CYP2D6 function (intermediate metabolizers). The alterations in stereoselectivity based on CYP2D6 activity likely have low clinical relevance. Bupropion and its metabolite levels were not affected by MDMA co-administration.
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.
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.
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.