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 |