New Pharmacological Approaches to the Treatment of Drug-resistant Depression – Placebo and Controlled Study with an Active Comparator.

According to the World Health Organization (WHO), depression is the fourth major cause of people’s health problems around the world. While available treatment is tolerated, its efficacy is limited. Approximately 20% – 30% of patients suffering from depression resist both medication and psychotherapy. Moreover, the negative side effects of antidepressants are decreasing its relevance.

Ketamine:

Recent research has increasingly focused on the short-term effect of the dissociated aesthetic of ketamine. Based on the available data and our own research (NUDZ), ketamine can be effective for patients for whom other methods do not work even in moderate doses, i.e. just enough to support the psychedelic effect . The disadvantage of ketamine is its duration of action, usually between 7 and 10 days. In terms of long-term use, it also has a problematic, addictive potential. The short-term effect of ketamine makes it a potentially suitable comparator for the possible long-term effects of psilocybin.

Ketamine is not the only psychedelic substance offering a potentially rapid effect for the treatment of anxiety and depression. A recent large-scale population study showed that people who have used psychedelics in the past have a lower incidence of psychiatric illnesses, psychological problems and even lower risk of suicide than those that have never taken psychedelics.

Another study, shows healthy volunteers the long-lasting positive effect of psychedelics on the mood and overall well-being of the study volunteers, among other things.

Psilocybin

Psilocybin is a serotoninergic psychedelic/hallucinogen, which naturally occurs in several species of mushroom around the world. Psilocybin is rapidly converted by the body to the active drug psilocin after use/administration. Psilocybin has been shown to meet safe standards for human subjects (e.g. NUDZ). The psychedelic effects of psilocybin are characterized by altered perception (illusions, pseudo hallucinations, hallucinations, synaesthesia, etc.), often with disturbed cognitive and emotional symptoms (such as euphoria, feelings of love, unity, but also anxiety, sadness, etc.). Evidence suggests that psilocybin may also have an effect on the neuroplasticity of the brain.

There are several theories of mechanisms that could be responsible for the antidepressant effect of psilocybin: 1) direct stimulation of serotonin receptors (the de facto antidepressant effect), 2) neuroplasticity (stimulation of new neuronal and neuronal connections), 3) the effect on the functional/state of the brain (psychedelics rapidly increase the number of processes in the brain, which seem to lead to the release of growth factors of new synaptic connections in the brain), 4) the psychological effect (the peak experience).

One of our assumptions is also a simple mechanical bond to neurogenesis: the longer the duration of the effect and/or the increased intensity of the psychedelic effects, the more likely it is that adaptive neuroplastic changes will occur, which, on the contrary, may be subject to antidepressant effects.

The main objective of this study is to conduct a Phase II clinical trial of antidepressant effects of psilocybin in the treatment of resistant depression (TRD). A secondary objective is to evaluate the neurobiology of the effects of antidepressants. The research will include a double-blind, placebo-controlled study comparing the prescribed doses of psilocybin (orally 20 mg), placebo (15 mg) and ketamine (orally 200 mg). The efficacy and safety of the oral administration of ketamine and midazolam has already been documented in our previous study.

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