LSD's rapid antidepressant effects are modulated by 5-HT2B receptors.
Amel Bouloufa, Sarah Delcourte, Renaud Rovera, Thomas Delannay, Alizée Duquet, Lionel Moulédous, Ouria Dkhissi-Benyahya, Bruno P. Guiard, Nasser Haddjeri
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie July 16, 2025 DOI: 10.1016/j.biopha.2025.118348 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Naive rats and naive mice |
| Intervention | LSD |
| Duration | Acute administration |
| Topics | Depression LSD Serotonin |
| Keywords | 5-ht2a Fast-acting antidepressants, 5-ht2b Hallucinogen Psychedelics Serotonin pathways serotonin Neuroscience research neuroscience |
| Citations | 12 |
| Key findings | Acute LSD induces fast antidepressant- and anxiolytic-like effects in rats, but not in mice, through mechanisms involving activation of 5-HT2B receptors. |
Abstract
Recent clinical trials show that serotonergic psychedelics, including the prototypical hallucinogen lysergic acid diethylamide (LSD), possess a great promise for treating affective disorders. Interestingly, LSD displays strong functional activity on 5-HT2B receptors and a modulatory role of the latter receptors in anxious and depressive-like behaviors has been reported. Using behavioral and in vivo electrophysiological tools in naive rats, the effects of acute administration of LSD were evaluated in the: forced swim test (FST), open field test, foot shock-induced ultrasonic vocalization, on the head-twitch response (HTR) and on the dorsal raphe serotonin 5-HT cell activity. By comparison, the antidepressant-, anxiolytic- and hallucinogenic-like effects of LSD were then assessed in naïve mice using the FST, the black & white box test and HTR. We show here that acute administration of LSD induced fast antidepressant-, anxiolytic- and hallucinatory-like effects as well as a suppression of 5-HT neuronal activity that were all counteracted by the selective pharmacological blockade of 5-HT2B receptors, including the potent and selective 5-HT2B receptors antagonist RS-127445. Interestingly, depletion of 5-HT prevented the action of LSD in FST and HTR. In contrast in mice, acute injection of LSD failed to produce an antidepressant- or anxiolytic-like response, and the hallucinogenic-like effect of LSD was not altered by a pretreatment with RS-127445. Together, these findings indicate that LSD, acutely administered, acts as a rapid-onset antidepressant in naïve rat, but not in naïve mice, through mechanisms involving activation of 5-HT2B receptors.
Comparable studies
Other preclinical and animal studies on LSD for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats | 2020 | Preclinical study | |
| A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Mice and cultured rat cortical neurons | 2023 | Preclinical study | |
| Repeated lysergic acid diethylamide in an animal model of depression: Normalisation of learning behaviour and hippocampal serotonin 5-HT2 signalling Male rats (olfactory bulbectomised and sham-operated) | 2014 | Animal model study | |
| 401. Prophylactic effects of LSD on inflammatory rodent model of depression Male mice and male rats | 2026 | Preclinical animal study |
Citations in the library
Cited by 11
- LSD: Mechanisms and relevance to the treatment of depression Neuroscience & Biobehavioral Reviews October 10, 2025
- Psilocybin-induced behavioral and cellular effects. Journal of neurogenetics July 12, 2026
- MFCC-DFT mapping of ligand recognition at the 5-HT2A receptor: energetic analysis of the interactions between serotonin, psychedelics, and antipsychotics. Physical chemistry chemical physics : PCCP July 1, 2026
- The Serotonin 2B (5‐ HT2B ) Receptor: A Narrative Review of Preclinical and Clinical Evidence on the Safety Considerations and Therapeutic Potential for the Treatment of Depression Clinical Pharmacology & Therapeutics May 28, 2026
- LSD persistently disrupts affective pain processing. bioRxiv : the preprint server for biology May 11, 2026
and 6 more in the library
Cites 41
- A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021
- Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors Science February 16, 2023
- Crystal structure of an LSD-bound human serotonin receptor Cell January 26, 2017
- The Pharmacology of Lysergic Acid Diethylamide: A Review CNS Neuroscience & Therapeutics November 11, 2008
- LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: A qualitative study of acute and sustained subjective effects Journal of Psychopharmacology November 11, 2014
and 36 more in the library