Psilocybin Superior to Ketamine for Prolonged Antidepressant-Like Effects (Rodent Model)

Results support the idea that serotonin 5-HT2A receptor-directed therapeutic strategies may be superior to ketamine-based treatments for depression.


Those paying attention to developments in psychedelic medicine in past years will have noticed the prominence of two compounds, in particular, psilocybin and ketamine. Though both compounds have demonstrated clinical efficacy in alleviating the symptoms of Treatment-Resistant Depression (TRD), they exert their therapeutic effects through different mechanisms of action.

Psilocybin is one of the many compounds found in so-called magic mushrooms (aka psilocybin mushrooms or psychedelic mushrooms). It is a prodrug of psilocin, the central compound responsible for the psychedelic effect.1 Psilocin binds to several serotonin receptors, including but not limited to 5-HT7, 5-HT2B, 5-HT2C and 5-HT2A.  Due to its established role in the psychedelic experience, current research primarily focuses on the 5-HT2A receptor.

Ketamine – used as a sedative and anesthetic in human and veterinary medicine – is an antagonist (i.e., blocker) of the NMDA (N-methyl-D-aspartate) receptor in neurons. Glutamate – the brain’s primary excitatory neurotransmitter- typically binds to the NMDA receptor. However, when ketamine blocks the receptor, glutamate can’t attach to it, thereby decreasing action potential conduction velocity. An action potential is a physiological process that facilitates the transmission of signals in neurons.

* Note that the basis of the therapeutic effect of both compounds is still debated within the scientific community. The hypotheses mentioned in this article represent the most prominent theories.

Setting the Stage for the Experiment

Despite their pharmacological differences, both psilocybin and ketamine demonstrate robust increases in neuroplasticity – the brain’s ability to reorganize itself by forming new neuronal connections. Many in the scientific community hypothesize changes in neuroplasticity underlie the fast-acting antidepressant (AD) properties of psychedelics. Similar changes in neuroplasticity are associated with conventional antidepressant treatment.2

One negative aspect of ketamine’s use in the clinic is abuse liability, and there are safety concerns linked with long-term use.3 Consequently, it is crucial to define the comparative efficacy of psilocybin and ketamine toward developing safe therapeutic approaches in the clinic for the treatment of depression. A recent study by Hibicke et al. of Louisiana State University set out to investigate these concerns, testing the safety and efficacy of the two compounds in alleviating depressive-like symptoms in a rat model.4

Study Design

The study used the Forced Swim Test (FST) to evaluate the antidepressant-like effects of the compounds. In the FST, mice are placed in an inescapable transparent tank filled with water, and escape related mobility behavior is measured. Immobility is interpreted as a passive coping strategy and labeled depressive-like behavior. Compounds that induce decreased immobility imply an antidepressant-like effect.

Many argue that the FST acts as a poor proxy for the depressive state, as the pathogenesis of the disease in humans stems from a multitude of factors (bereavement, genetics, abuse, socio-economic class, etc.). However, numerous AD treatments have been demonstrated to frequently alleviate the depression-like symptoms exhibited by animals in the test, highlighting the FST predictive validity as a primary screening test for AD.5

For the dosing prior to conducting the FST, researchers injected rats with either psilocybin (1 mg/kg), ketamine (5 mg/kg), or saline.

To test the anxiolytic (anxiety-reducing) effect of the two compounds, the study used another staple in behavioral pharmacology, the elevated plus-maze (EPM). This is an apparatus consisting of four equally sized arms, two of which are open runways and two of which are enclosed by walls.

The behavioral model is based on the aversion of rodents to open spaces. This aversion drives the animals to find refuge in enclosed spaces or close to the edges of a confined space. In the EPM, this behavior manifests when animals limit their movements to the enclosed arms. An increased proportion of time spent in the open arms indicates anxiety reduction.

Psilocybin Demonstrates Superior Antidepressant-Like Effects

Animals injected with psilocybin displayed decreased immobility in the FST when compared with the control group 5 weeks after administration (the conclusion of the experiment), symbolizing an antidepressive-like effect. Furthermore, there was no sign of the effects diminishing over time, indicating that the therapeutic effects of a single dose of psilocybin likely last far beyond the five weeks.

Rats administered ketamine displayed significantly decreased immobility compared to the control group when tested at weeks one and two. However, the drug’s durability waned, with immobility increasing at week 3 to the point where it was indistinguishable from the saline-treated animals.

The authors state that these results agree with clinical studies in humans described in the literature. The human studies demonstrate a long-lasting therapeutic effect of psilocybin following a single-administration, compared to the relatively transient antidepressant effect of ketamine.

Measuring the Impact of Setting

The researchers added an intriguing aspect to this experiment. Reports from clinical research on psilocybin in humans outline a correlation between an individual’s subjective experience and the clinical efficacy of the treatment. Moreover, how well patients respond to treatment is dependant on ‘set and setting.’ Set refers to the mental state a person brings to the experience. Setting refers to the physical and social environment in which the psychedelic experience takes place.

While the researchers could not directly examine the subjective experience of the animals, they developed a proxy for the setting aspect. A proportion of the psilocybin-dosed rats were exposed to an open field arena 5 minutes per week for the first three weeks. The open field is an arena surround by walls to prevent escape. It represents an anxiety-inducing environment for the animals as they have an aversion to open, brightly lit areas.

Anxiolytic Effects and Context

Both psilocybin and ketamine treated animals completed the EPM at the conclusion of the experiment in week 5. Interestingly, the data revealed the following:

  • Rats receiving psilocybin and weekly arena exposure exhibited significantly less anxiety-like behavior in the EPM compared to controls.
  • Rats receiving ketamine and weekly arena exposure did not display a significant decrease in anxiety in the EPM.
  • Rats receiving psilocybin or ketamine and no arena exposure did not display a significant decrease in anxiety in the EPM.

These results shed light on how environmental factors also play a critical role in the drug’s anxiolytic effects. The authors write:

Our results suggest that psilocybin facilitates a period of behavioral flexibility in which exploration of a non-home-cage environment reduces their anxiety during future exploration of a novel environment…In this context, psilocybin may open a window during which time certain experiences are salient to the development of new coping strategies.

Why Are These Findings Important? 

Many criticize the translatability of animal studies and the validity of behavioral tests as representative of neuropsychiatric disease states. How can a handful of tests conducted in specific conditions represent the etiology of such complex, multi-factorial disease states such as depression and anxiety? The honest answer is, they can’t.

However, these behavioral paradigms have strong predictive validity. In other words, they accurately predict how well the outcomes of drug studies in the model predict the action of drugs.

Taking this into account, the study demonstrates the more persistent therapeutic effects of a single administration of psilocybin compared to ketamine and supports the idea that serotonin 5-HT2A receptor directed therapeutic strategies may be superior to ketamine-based treatments in the clinic for depression.

Furthermore, the authors question whether the therapeutic effects of psilocybin are dependent on the individuals’ subjective “peak” experience or are physiological in nature with the peak experience merely serving as a biomarker for antidepressant efficacy.

As far as is known, the animals tested in this experiment do not possess the capacity to contextualize their psychedelic experience and appropriate that information to improve their affective state.  Therefore, the authors of the paper claim that the basis for the antidepressant effects is at its core biological in nature, with ego dissolution representing a correlative rather than a causal marker of therapeutic outcome.


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Andrew Chadeayne
3 years ago

Thanks for the great article. Isn’t it also interesting how the most recent (2020) study by Nichols et al. compares the effects of LSD with that of psilocybin, noting that “psilocybin’s effect size (d= 4.985) was far greater than LSD’s(d= 0.863)…” and that “there was no indication of the effects decreasing over time, suggesting that the therapeutic effects of a single administration of psilocybin likely last far beyond the 5 weeks we tested.” See page 865 at Results and Discussion. Taken together, it seems pretty clear that not all psychedelics have the same clinical benefits.