Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice

This mice study found that the anti-depressant effects from psilocybin (1mg/kg) are possibly independent of the psychedelic/hallucinogen effects by pre-treating the mice with ketanserin (which blocks the acute effects) and finding similar anti-depressant effects as in the psilocybin only group (measured through activity patterns and synaptic action).


“Depression is a widespread and devastating mental illness and the search for rapid-acting antidepressants remains critical. There is now exciting evidence that the psychedelic compound psilocybin produces not only powerful alterations of consciousness, but also rapid and persistent antidepressant effects. How psilocybin exerts its therapeutic actions is not known, but it is widely presumed that these actions require altered consciousness, which is known to be dependent on serotonin 2A receptor (5-HT2AR) activation. This hypothesis has never been tested, however. We therefore asked whether psilocybin would exert antidepressant-like responses in mice and, if so, whether these responses required 5-HT2AR activation. Using chronically stressed male mice, we observed that a single injection of psilocybin reversed anhedonic responses assessed with the sucrose preference and female urine preference tests. The antianhedonic response to psilocybin was accompanied by a strengthening of excitatory synapses in the hippocampus—a characteristic of traditional and fast-acting antidepressants. Neither behavioral nor electrophysiological responses to psilocybin were prevented by pretreatment with the 5-HT2A/2C antagonist ketanserin, despite positive evidence of ketanserin’s efficacy. We conclude that psilocybin’s mechanism of antidepressant action can be studied in animal models and suggest that altered perception may not be required for its antidepressant effects. We further suggest that a 5-HT2AR–independent restoration of synaptic strength in cortico-mesolimbic reward circuits may contribute to its antidepressant action. The possibility of combining psychedelic compounds and a 5-HT2AR antagonist offers a potential means to increase their acceptance and clinical utility and should be studied in human depression.”

Authors: Natalie Hesselgrave, Timothy A. Troppoli, Andreas B. Wulff, Anthony B. Cole & Scott M. Thompson


This study was featured in a press release by the University of Maryland and also examined on Psychedelic Science Review, and a video by Asher Brandt.

Multiple articles in recent years have been investigating this line of thought, with Cameron and colleagues (2020) being the most prominent. If psychedelics (or analogs of them) can have antidepressant effects (for now in mice) without the need for many hours of therapy (during the acute effects), would that possibly make them cheaper and more accessible?

“If 5-HT2AR activation is not necessary, then the combination of psilocybin and a 5-HT2AR antagonist safe for human use, such as ketanserin, offers a potential means to eliminate, attenuate, or shorten the duration of psilocybin-induced alterations of perception while retaining its therapeutic benefits.”

One hypothesis that this paper puts forth, is that psilocybin may elicit its anti-depressive effects through other serotonin (5-HT) receptors than the 5-HT2A receptors. As ketanserin blocks the effect of psilocybin on this receptor, it is hypothesized that other receptors such as the 5HT1B or AMPA receptors could be responsible for the observed effects.

The Study

Mice (8 weeks old, C57BL/6J) were chronically exposed to stress. Normally they would be attracted to water with sucrose (think Gatorade) and female urine. Both these urges were suppressed after chronic stress exposure.

The study was broken into four different groups. The first group received nothing (but stress). The second group only received ketanserin. The third group received only psilocybin. And the fourth group received ketanserin and psilocybin.

The mice in the last two groups significantly improved their urges, whilst in the last group, there were no signs of activation of the 5-HT2A receptor (as indicated by the head-twitch response, usually also seen as a proxy for psychedelic/hallucinogenic effects).

“Significant improvements in both sucrose and female urine sniffing preferences were observed in mice having both few and many head twitches, consistent with our conclusion that the restoration of reward behavior by psilocybin was independent of 5-HT2AR activation.”

When investigating the brainwaves of the mice, the researchers “observed that ketanserin pretreatment greatly attenuated the decrease in LFP delta power in response to this high concentration of psilocybin, providing another strong positive control of its efficacy as a 5-HT2AR antagonist in the hippocampus under our experimental conditions.” The structural strengthening of synapses in the brain (also named functional connectivity in humans) is possibly responsible for the anti-depressant effects of psilocybin/psychedelics. The effect on AMPA/NMDA ratios were not influenced by the pretreatment with ketanserin.

Finally, the study looked at the forced swim test, but found no effects here (it does look to be a different group of mice and not using ketanserin here; see figure 4 in the appendix).

Limitations and Implications

To be clear, this study was done in mice and should be replicated in humans. The effects were only observed up to 48 hours later and the effects of a psychedelic experience may still be needed for enduring effects.

Still, this paper indicates that the acute psychedelic experience may not be necessary which could greatly increase access.

In the future, new compounds can be made that specifically target synaptic strengthening with fewer perceptual effects.

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