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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
BMC pharmacology & toxicology
May 26, 2016
Evangelia Liakoni, Patrick C. Dolder, Katharina 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.
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.
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.
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.