Ketanserin exhibits dose- and concentration-proportional serotonin 2A receptor occupancy in healthy individuals: Relevance for psychedelic research
Friederike Holze, M. Madsen, Claus Svarer, Nic Gillings, Dea Siggaard Stenbæk, Deborah Rudin, Urs Duthaler, Matthias E. Liechti, Patrick M. Fisher, Gitte M. Knudsen
European Neuropsychopharmacology August 9, 2024 DOI: 10.1016/j.euroneuro.2024.07.003 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Positron emission tomography (PET) study Peer reviewed |
|---|---|
| Population | Healthy participants |
| Intervention | Ketanserin |
| Dose | 10, 20, or 40 mg |
| Measures | binding potential (BPND), simplified reference tissue model (SRTM) |
| Topics | Serotonin |
| Keywords | Ketanserin Occupancy 5-HT Receptor Relevance law |
| Citations | 16 |
| Key points | Peroral ketanserin intake resulted in a plasma concentration-related increase in cerebral 5-HT2A receptor occupancy, with an EC50 of 2.52 ng/mL corresponding to approximately 10 mg oral dose. |
Abstract
The serotonin 2A (5-HT2A) receptor is an important target for drug development and the main receptor through which classical psychedelics elucidate their hallucinogenic effects. The 5-HT2A receptor antagonist ketanserin has frequently been used as a tool to block the receptor. Here, we establish the dose-occupancy relation of ketanserin and the cerebral 5-HT2A receptor in healthy participants by conducting a positron emission tomography (PET) study. 120-min PET scans using the 5-HT2A receptor agonist radiotracer [11C]Cimbi-36 were conducted at baseline and after oral doses of either 10, 20, or 40 mg of ketanserin; each participant underwent one or two scans after ketanserin administration. Occupancy was defined as the percent change in neocortex binding potential (BPND), estimated using the simplified reference tissue model (SRTM) with the cerebellum as reference region. Peroral ketanserin intake resulted in a plasma concentration-related increase in cerebral 5-HT2A receptor occupancy with the highest plasma ketanserin concentrations measured after ∼2 h. The relation between mean plasma ketanserin concentrations and 5-HT2A receptor occupancy conformed to a single-site binding model with an estimated EC50 (95 % CI) of 2.52 (0.75; 8.1) ng/mL, which corresponds to a peroral dose of ketanserin of approximately 10 mg. These data elucidate for the first time in humans the cerebral pharmacodynamics of ketanserin, both benefitting its use as a pharmacological tool for probing brain function and adding to its potential for therapeutic use in rescuing a bad psychedelic experience.
Comparable studies
Other experimental studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers | 1998 | Experimental study | |
| Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | 2000 | Experimental study | |
| Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Rat brain | 1988 | Experimental study | |
| The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Human platelet plasma membrane vesicles and bovine adrenal chromaffin granule membrane... | 1992 | Laboratory study | |
| 5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex Rat brain | 1997 | Experimental study |
Citations in the library
Cited by 11
- Psychedelics, entactogens and psychoplastogens for depression and related disorders British Journal of Pharmacology June 15, 2025
- Acute psilocybin and ketanserin effects on cerebral blood flow: 5-HT2AR neuromodulation in healthy humans. Journal of Cerebral Blood Flow & Metabolism February 26, 2025
- Neuropsychopharmacology of hallucinogenic and non-hallucinogenic 5-HT2A receptor agonists. British Journal of Pharmacology May 23, 2025
- Psychedelic Drugs in Mental Disorders: Current Clinical Scope and Deep Learning‐Based Advanced Perspectives Advanced Science March 20, 2025
- Above the threshold, beyond the trip: the role of the 5-HT2A receptor in psychedelic-induced neuroplasticity and antidepressant effects Molecular Psychiatry August 23, 2025
and 6 more in the library
Cites 8
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels Neuropsychopharmacology January 26, 2019
- Lysergic Acid Diethylamide-Assisted Therapy in Patients With Anxiety With and Without a Life-Threatening Illness: A Randomized, Double-Blind, Placebo-Controlled Phase II Study. Biological Psychiatry February 1, 2023
- Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects Neuropsychopharmacology October 15, 2020
- Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects Neuropsychopharmacology February 25, 2022
and 3 more in the library