Clinical pharmacokinetics
July 14, 2025
Lorenz Mueller, Aaron Klaiber, Laura Ley et al.
4 citations
Mescaline, a classic psychedelic, shows dose-proportional increases in blood concentration and effects after oral administration. Peak levels occur within about 2 hours, with a half-life of 3.5 hours. Effects begin around 1 hour after dosing, with intensity and duration increasing from 13% and 2.8 hours at 100 mg to 89% and 15 hours at 800 mg. About 53% of the dose is excreted unchanged in urine, and 31% as a main metabolite. Oral bioavailability is at least 53%, limited by first-pass metabolism, with renal elimination as the primary clearance route.
Drug metabolism and disposition: the biological fate of chemicals
April 28, 2025
Jan Thomann, Deborah Rudin, Selina Kraus et al.
4 citations
A liquid chromatography-tandem mass spectrometry method was developed and validated to measure the recreational psychedelic 2C-B and two of its metabolites (BDMPAA and B-2-HMPAA) in human plasma. The method achieved linear ranges of 0.5–100 ng/mL for 2C-B, 2.5–1000 ng/mL for BDMPAA, and 0.5–1000 ng/mL for B-2-HMPAA with high accuracy and precision. Pharmacokinetic analysis used samples from clinical participants who received 30 mg of 2C-B. Key metabolic enzymes included MAO-A, MAO-B, cytosolic enzymes, and CYP2D6. Unlike 2C-B, the metabolites did not activate the serotonin 2A receptor, indicating they do not contribute to the psychedelic effect. The method provides a reliable tool for future clinical studies.
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.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
July 1, 2026
Denis Arikci, Joran Borgulya, Isabelle Straumann et al.
1 citation
In a double-blind, randomized, placebo-controlled crossover trial, 24 healthy adults received three doses of 2C-B (10, 20, and 30 mg), 125 mg MDMA, and 25 mg psilocybin. The 30 mg dose of 2C-B produced subjective effects comparable to MDMA but weaker than psilocybin, and increased emotional empathy similarly to MDMA. Only psilocybin caused bad drug effects and anxiety. MDMA produced the greatest cardiovascular stimulation, followed by psilocybin and then 2C-B. Only MDMA raised plasma oxytocin and neurophysin I. The average subjective effect duration of 30 mg 2C-B was 4.9 hours, similar to MDMA (4.8 h) and shorter than psilocybin (6.1 h). 2C-B had a plasma elimination half-life of about 1.3 hours.
Frontiers in Pharmacology
November 20, 2025
Karolina E. Kolaczynska, Daniel Trachsel, Marius C. Hoener et al.
1 citation
A class of psychedelic compounds called 4-substituted 2,6-dimethoxyphenethylamines and their amphetamine counterparts (Ψ derivatives) were tested for their interactions with monoamine receptors and transporters. These derivatives showed moderate to high affinity and activity at the human 5-HT2A receptor, the primary target for psychedelics, with binding affinities ranging from 8 to 1,600 nM and activation potencies from 32 to 3,400 nM. They acted as partial agonists at this receptor. The phenethylamine derivatives also bound to 5-HT1A and 5-HT2C receptors with moderate affinity, while amphetamine derivatives had weaker affinities. Some Ψ derivatives interacted with TAAR1 and adrenergic receptors. Compared to 2,4,5-trisubstituted derivatives, the 2,4,6-trisubstituted Ψ derivatives were generally less potent at the 5-HT2A receptor but more potent than 3,4,5-trisubstituted derivatives.
Molecular Psychiatry
November 5, 2025
Dino Luethi, Grant C. Glatfelter, Eline Pottie et al.
1 citation
Psychedelic-like effects of ring-substituted amphetamines are primarily mediated by 5-HT 2A receptors. Small lipophilic substituents at the 4-position of 2,5-dimethoxyamphetamine enhance clinical potency. This study examined 4-alkylated 2,5-dimethoxyamphetamines (methyl, ethyl, propyl, butyl, amyl) for in vitro receptor activity and in vivo effects in mice using the head-twitch response (HTR) assay. Increasing 4-alkyl chain length raised affinity at 5-HT 2A receptors. The 4-propyl analog showed the highest potencies for 5-HT 2A receptor activation (1–9 nM) in vitro; other chain lengths ranged from 2–56 nM. In mice, maximal HTR counts varied from 23 to 119, with potencies from 0.42 to 2.76 mg/kg.
Biomedical chromatography : BMC
September 1, 2025
Jan Thomann, Selina Kraus, Livio Erne et al.
1 citation
A new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method accurately measures ketamine and its metabolites norketamine, dehydronorketamine (DHNK), and (2R,6R)-hydroxynorketamine (HNK) in human plasma. The method uses a small sample volume, a simple protein precipitation step, and a fast run time. Linear quantification ranges were 1-1,000 ng/mL for ketamine and norketamine, 0.25-100 ng/mL for DHNK, and 2.5-1,000 ng/mL for (2R,6R)-HNK. The method showed high accuracy, precision, selectivity, and sensitivity, with consistent matrix effects and efficient extraction recovery. It was successfully applied to assess pharmacokinetics in six clinical trial participants, offering a robust approach for clinical studies, drug monitoring, and forensic investigations.
Frontiers in Psychiatry
January 4, 2023
Felix P. Mayer, Dino Luethi, Lorena B. Areal et al.
1 citation
Psychoactive substances have been consumed throughout human history, first from plants and fungi, then isolated compounds like cocaine, and later synthetic drugs such as LSD. Many recreational drugs also have clinical uses, e.g., amphetamines for ADHD. New psychoactive substances (NPS) have expanded the drug market and improved understanding of structure-activity relationships. Recent clinical trials are reevaluating psychedelics like psilocybin and MDMA for conditions such as depression and PTSD. This special issue includes studies on synthetic opioids, NBOMe derivatives, psilocybin's anxiolytic effects in healthy volunteers, psilocybin reducing body weight in obese rats, and reviews linking mystical experiences to symptom reduction. The collection highlights both risks and therapeutic potential of psychoactive compounds.
Translational Psychiatry
June 4, 2026
Mélusine Humbert‐droz, Anna M. Becker, Jan Valenta et al.
A booster dose of MDMA prolongs the acute subjective drug effects compared with a single dose, without increasing peak effects. In a double-blind, randomized, placebo-controlled crossover study with 23 healthy volunteers, a 120 mg dose of MDMA followed by a 60 mg booster after 2 hours extended the duration of subjective effects to an average of 5.6 hours, versus 4.6 hours with a single dose. Adverse effects were more common after both MDMA conditions than placebo. Whether the prolonged effect translates into clinical benefit for MDMA-assisted psychotherapy remains unknown.
British Journal of Pharmacology
May 5, 2026
Giorgia Corli, Deborah Rudin, Dino Luethi et al.
Some new synthetic cannabinoid receptor agonists (SCRAs) also directly activate the serotonin 5-HT₂A receptor, which may contribute to unexpected psychiatric side effects. Many SCRAs with a valinamide or tert-leucinamide head moiety showed in vitro activity at the 5-HT₂A receptor at high concentrations. In mice, the compound AB-5′F-BUTINACA caused neurological changes, sensorimotor alteration, antinociception, hypothermia, reduced breath rate, and hypolocomotion. These effects were mediated by both CB₁ and 5-HT₂A receptors, as they were prevented by selective antagonists. The findings indicate potential risks of SCRA consumption that could exacerbate unexpected psychiatric conditions.
Translational Psychiatry
March 27, 2026
Livio Erne, Lorenz Mueller, Isabelle Straumann et al.
Bolus injections of DMT produce very strong subjective effects that peak within 2 minutes and subside completely within 12–30 minutes, consistent with a short elimination half-life of about 6–7 minutes. A ceiling effect for peak subjective effects occurred at the 15 mg dose, and no tolerance developed to the acute effects. Tolerability markedly improved when doses were escalated openly rather than given double-blind, and at equivalent doses the subjective effects were rated as less intense. These results indicate that blinding and expectancy influence the subjective experience and that individual dose-escalation may improve tolerability and guide dose selection in future DMT studies.
The FASEB Journal
May 1, 2022
Deborah Rudin, Dino Luethi, Marius C. Hoener et al.
4-Halogenated derivatives of 2,5-dimethoxyamphetamine (DOX) show increasing selectivity for the 5-HT2A receptor as the halogen size increases, with DOI exhibiting nearly 1000-fold higher selectivity than DOF. All tested derivatives acted as partial to full agonists at the 5-HT2A receptor. Their 5-HT2 receptor interaction potency resembled that of their 2C analogues, but with greater 5-HT2A versus 5-HT1A selectivity. None showed nanomolar affinity for TAAR1, adrenergic, dopaminergic, or monoamine transporters. This enhanced selectivity may explain the higher clinical potency of DOX derivatives but could also increase seizure risk, suggesting 2C derivatives may be safer for clinical applications.
The FASEB Journal
May 1, 2022
Dino Luethi, Deborah Rudin, Marius C. Hoener et al.
The pharmacological properties of 4-alkylated 2,5-dimethoxyamphetamines were examined in vitro, focusing on how the length of the 4-alkyl chain affects interactions with monoaminergic targets. The 4-alkylated derivatives (DOM, DOET, DOBU, DOAM) showed potent nanomolar affinity at serotonin 5-HT2A and 5-HT2C receptors, unlike the parent compound 2,5-DMA. Increasing alkyl chain length enhanced selectivity for 5-HT2A over 5-HT1A and 5-HT2C receptors. DOM and DOET activated the 5-HT2B receptor as partial agonists (EC50: 68–128 nM, Emax: 73–85%), while DOBU and DOAM did not (EC50 > 10,000 nM). The derivatives showed weak or no interaction with other monoaminergic targets. The findings suggest that 5-HT2A and 5-HT2C receptor affinity alone does not sufficiently predict clinical or psychedelic potency.
The International Journal of Neuropsychopharmacology
May 24, 2018
Dino Luethi, Matthias E Liechti
Rapidly measuring the in vitro pharmacological activity of new psychoactive substances can help predict their psychoactive doses and effects in humans, aiding in the appropriate legal scheduling of these substances.
The FASEB Journal
April 1, 2018
Matthias E. Liechti, Dino Luethi
For amphetamine-type novel psychoactive substances (NPS), the potency of inhibiting the norepinephrine transporter (NET) in cells correlated significantly with the doses people typically use to get psychoactive effects, while inhibition of dopamine or serotonin transporters did not. For hallucinogenic NPS and classic hallucinogens (tryptamines, phenethylamines), binding affinity at the serotonin 5-HT2A receptor strongly predicted human psychoactive dose; binding at 5-HT2C did so less strongly, and 5-HT1A showed no relationship. In vitro pharmacological profiling of NET inhibition and 5-HT2 receptor binding may help estimate psychoactive doses of new substances, though factors like metabolism and brain penetration also matter.