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.
Clinical toxicology (Philadelphia, Pa.)
March 1, 2025
Joep J. J. Ouwerkerk, David M. Wood, Alison M. Dines et al.
1 citation
When 3,4-methylenedioxymetamfetamine (MDMA) is taken with alcohol, emergency department visits show higher odds of agitation, drowsiness, and vomiting compared to MDMA alone. Co-intoxication with other substances increases odds of bradycardia, psychosis, and coma. Mortality rates remain low across all groups. Female patients report less chest pain but more vomiting, headache, and hypotension than males. These variations suggest that physicians should consider both the type of co-intoxication and patient sex to optimize treatment.
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.
Repository for Publications and Research Data (ETH Zurich)
April 30, 2026
Kurt Stocker, Matthias Hartmann, Frederick S. Barrett et al.
The Psychedelic Experience Scale (PES48) has an eight-factor structure that includes the well-validated Mystical Experience Questionnaire (MEQ30) plus four additional factors: paradoxicality, connectedness, visual experience, and distressing experience. This study tested whether the full eight-factor structure is valid in English, using data from 280 PES measurements from 145 healthy participants in four placebo-controlled psilocybin studies. Six of the eight subscales showed high internal consistency, one good, and one acceptable. Confirmatory factor analysis indicated acceptable to good model fits for the MEQ30 and MEQ40, with English data showing better fits than the German validation sample. The findings suggest the PES48 is a valid psychometric tool in English, enabling broader measurement of mystical and non-mystical aspects of psychedelic experience.
Religion Brain & Behavior
March 31, 2026
Kurt Stocker, Matthias Hartmann, Frederick S. Barrett et al.
After administration of LSD, psilocybin, mescaline, or DMT, mystical oneness—the core of mystical experience—showed dose-sensitive strong correlations with luminous light and renewal, and a moderate-to-strong correlation with ego disintegration. These findings from 386 healthy participants across 15 studies support a broader, dynamic model of mystical experience, where mystical oneness unfolds with ego disintegration, renewal, and luminous light. The results offer insights for psychedelic-assisted therapy.
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.
Repository for Publications and Research Data (ETH Zurich)
January 1, 2026
Kurt Stocker, Matthias Hartmann, Frederick S. Barrett et al.
Mystical oneness after psychedelics is linked to ego disintegration, renewal, and luminous light, and these connections intensify with higher doses. Analyzing 816 measurements from 386 healthy participants given LSD, psilocybin, mescaline, or DMT across 15 studies, researchers found dose-sensitive strong correlations between mystical oneness and luminous light and renewal, and a moderate-to-strong correlation with ego disintegration. The results support a dynamic model of mystical experience and suggest relevance for psychedelic-assisted therapy.
Br J Pain
September 4, 2025
Mauro Cavarra, Nadia R. P. W. Hutten, Jan Schepers et al.
A single 15 μg dose of lysergic acid diethylamide (LSD) did not significantly alter pain perception in healthy volunteers compared to placebo in a randomized controlled trial. The study used a double-blind design to test whether a microdose of LSD would produce analgesic effects, but found no meaningful difference between the LSD and placebo conditions on measures of pain tolerance or threshold.
Repository for Publications and Research Data
January 1, 2025
Kurt Stocker, Matthias Hartmann, Schmid, Yasmin et al.
The Altered States of Consciousness Scale (ASC), commonly used in psychedelic research, has two incompatible scoring systems: a three-dimensional model (3D-ASC) and an eleven-subscale model (11-ASC). Analyzing data from 901 questionnaires across 16 psychedelic studies, researchers found that ten of the eleven subscales could be reorganized into three higher-order dimensions—Positive, Distressing, and Perceptual effects—that closely mirror the original three dimensions but with improved statistical fit. This revised version, called the 3D-ASCr, retains the Anxiety subscale separately due to floor effects. The 3D-ASCr is recommended for use with classic serotonergic psychedelics in clinical practice and research.
Front Psychiatry
October 25, 2023
Steffen Reissmann, Matthias Hartmann, Andreas Kist et al.
In a single patient with treatment-resistant depression, personalized dosing of ketamine infusions that consistently maintained an altered state of consciousness was associated with sustained antidepressant relief over repeated sessions. The patient received six infusions over three weeks, with doses adjusted to keep the altered state at a moderate-to-strong level. Depressive symptoms dropped by more than 50% after the first infusion and remained low for at least four weeks after the final infusion. The case suggests that maintaining a non-ordinary state of consciousness across infusions may be important for long-lasting antidepressant effects.
Journal of the Endocrine Society
October 1, 2023
Cihan Atila, Friederike Holze, Rakithan Murugesu et al.
Patients with arginine vasopressin deficiency (central diabetes insipidus) show heightened anxiety, alexithymia, and depressed mood at baseline compared with healthy controls. When given a single 100 mg oral dose of MDMA, patients had only a minimal oxytocin increase of 66 pg/ml, whereas healthy controls showed an increase of 658 pg/ml—a 15.8-fold difference. This blunted oxytocin response was accompanied by reduced subjective effects including trust, happiness, openness, and fear reduction. The findings suggest that an oxytocin deficiency may underlie the psychological symptoms in these patients, establishing oxytocin deficiency as a potential hypothalamic-pituitary entity.
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 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
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.