Psilocybin vs Ketamine in the Treatment of Depression

Does psilocybin provide hope to patients with severe depression?

Czech researchers are also trying to answer this question. Almost immediate onset of action after a single administration and minimal side effects, these are the main advantages of so-called “fast-acting antidepressants”. Their main representatives are the dissociative anesthetic ketamine and the psychedelic psilocybin. The onset of action of traditional antidepressants is in the order of many weeks. Patients often have to try more than a single drug, and about one third of all patients do not experience any relief. At the same time, depression is one of the most common causes of incapacity and illness in the population. Psychedelic assisted therapy offers a revolutionary approach to the treatment of this insidious disease. Czech researchers were the first in the world to obtain approval for a clinical trial (study) in patients with treatment-resistant depression, in which they would compare the effects of psilocybin, a substance naturally occurring in hallucinogenic mushrooms, with ketamine, which is already a registered antidepressant. The main objective of this study is to evaluate the rate of onset of the antidepressant effects of both substances and the time for which the effects persist. Researchers will also use simultaneous state-of-the-art recording of brain activity using EEG and magnetic resonance imaging to determine which mechanisms these substances use to induce antidepressant effects.

Psilocybin versus ketamine – fast acting antidepressant strategies in treatment-resistant depression (PSIKET001_CZE)

EUDRACT No:  2018‐004480‐31



According to the World Health Organization (WHO), the lifetime prevalence of depression in the population is between 8-12%, and worldwide, depression is the fourth most common cause of work incapacity. Therefore, research of new treatment strategies, including the use of older effective, albeit currently unused, treatments is essential. The currently used treatments for depressive disorders face two major problems. The first of these is the high drug resistance of patients to treatment, where 20-30% of patients are resistant to both pharmacological treatment and cognitive behavioral therapy. At the same time, it has been shown that many of the side effects of the current antidepressants can do more harm than good to the patient. Many patients also fail with other types of treatment, including psychotherapy and non-pharmacological treatment, such as electroconvulsive therapy or other stimulation methods. The second problem is the long time from the start of treatment to the full onset of antidepressant effects. This typically ranges from 4-8 weeks after the introduction of the full therapeutic dose, and if we take into account that the patient does not respond to even three adequate treatments, it can be up to 24 weeks, during which time the patient is often incapacitated and often hospitalized.

New treatment strategies, which will allow a breakthrough in resistance and in which the onset of effects is much shorter than with “classical” antidepressant pharmacotherapy, are essential. These are rapid antidepressant treatment strategies, among which the drug ketamine currently has a dominant position. At present, the treatment of depression with the use of ketamine is one of the approved treatments in both the EU and the USA. A new strategy is the use of so-called serotonergic psychedelics, especially psilocybin. Studies using this substance consistently describe a positive effect on mood and anxiety with minimal side effects. In addition, psilocybin treatment was awarded the status of a breakthrough therapy in 2019 from the US regulatory authorities (FDA) for both resistant and common depression.


Psychedelics are substances with very specific psychological effects, inducing altered states of consciousness (ASC), which are characterized by changes in the level of perception, thinking and emotion. Psilocybin is a serotonergic psychedelic/hallucinogen that occurs ubiquitously in various species of hallucinogenic mushrooms, known primarily as magic mushrooms. Psilocybin has been administered safely to healthy people and patients in a number of studies, including at the National Institute of Mental Health (NÚDZ), and is one of the most suitable candidates for concurrent psychotherapeutic work in psychedelic-assisted therapy due to its medium duration of action. The psychedelic effects of psilocybin are characterized by altered perception (illusions, pseudo hallucinations, hallucinations, synesthesia, etc.), and we often encounter impaired cognitive and emotional symptoms (such as euphoria, feelings of love, unity, but also anxiety, sadness, etc.). The antidepressant effect of serotonergic psychedelics, including psilocybin, is now thought to be due to a direct effect on brain neuroplasticity, and in particular a positive effect on the formation of new connections between neurons.


Ketamine has been used in medicine for a relatively long time as a general anesthetic for diagnostic and short surgical procedures and also in lower doses for pain relief. Its safety in humans has been confirmed through over 30 years of use, especially in pediatric anesthesiology. The latest findings on ketamine show its strong antidepressant effects, which start almost immediately after application, and it usually takes 7-10 days for depressive symptoms to improve or disappear. According to the available studies, subanesthetic doses, i.e. those that support the psychedelic effect, prove to be effective even in patients in whom other methods of treatment have not worked. Our findings and others from abroad confirm the fact that the antidepressant effect depends on the intensity of the psychedelic experience. The basis is probably again a positive effect on the neuroplasticity of the brain. The disadvantage of ketamine is the already mentioned relatively short duration of the antidepressant effect (7-10 days) and also the possible potential for addiction. However, the short-term effect of ketamine makes it a potentially suitable comparator for studying the antidepressant effect of psilocybin.


There are several theories of the mechanisms that may be behind the antidepressant effect of psilocybin. 1) direct influence on serotonin receptors (opposite of antidepressant effect) 2) increased neuroplasticity (psychedelics increase the number of neuronal connections in the brain), 3) influence on functional states of the human brain (they can switch the brain from one state to another that is functionally/energetically more benefited) 4) psychological effect (transformative potential of psychedelic experiences)

One of our assumptions is a simple mechanistic link to neuroplasticity: the longer the duration of action and/or the increased intensity of psychedelic effects, the more likely it is that adaptive neuroplastic changes will occur, which may in turn be subject to antidepressant effects.


The main objective of this project is to implement a phase II clinical trial of the antidepressant effects of psilocybin in the treatment of resistant depression (TRD), through a double-blind, placebo and active comparator-controlled study comparing the effect of psychedelic doses of psilocybin (20 mg) to an active placebo midazolam (15 mg) and active comparator ketamine (200 mg). The secondary objective is to investigate the neurobiology of the antidepressant effect of psilocybin using the methods of quantitative electroencephalography and functional magnetic resonance imaging of the brain.

The expected benefit of treatment is the breakdown of drug resistance, an improvement to clinical signs of depression and a significantly faster onset of action compared to conventional antidepressants.


The psilocybin vs ketamine (PSIKET) study is a randomized, controlled phase II clinical trial aimed at determining the efficacy and safety of psilocybin in adult patients with moderate to severe drug-resistant depression. A total of 60 patients will be randomized to three parallel treatment arms: psilocybin 20 mg (active substance 1), ketamine (active substance 2/positive control) and midazolam (negative control). The active phase of the study will take place during hospitalization at NÚDZ and the study medication will be administered once orally in the form of capsules during drug-assisted psychotherapy. Follow-up of patients will take place in the form of outpatient visits at regular intervals for one year.



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