PAP: You received a recommendation for funding to the amount of PLN 16 million from the Medical Research Agency to conduct a clinical trial assessing the effectiveness and safety of psilocybin administered in combination with SSRI drugs (selective serotonin reuptake inhibitors) or after their discontinuation in patients with drug-resistant depression. As far as I know, more research centres in Poland have applied for approval of such research. How did you manage to do it?

Magdalena Więdłocha (Department of Psychiatry of the Faculty of Health Sciences, Medical University of Warsaw): Our research project was positively assessed by experts in the Medical Research Agency competition for non-commercial clinical trials and was among 21 projects recommended for funding. However, I must clarify that we do not yet have permission to conduct the trial. Obtaining permission for the study from the committee at the European Medicines Agency (EMA) is the first stage of this project.

PAP: Psilocybin is on the list of controlled substances, so obtaining permission for research is not that easy.

Piotr Marcinowicz (KeyClinic Psychiatry and Psychotherapy Centre): This is a substance from the I-P group, which can only be used for the purpose of conducting scientific research and is completely excluded from circulation. As a scientific unit, the Medical University of Warsaw, which is the leader of this project, can receive permission to conduct psilocybin research.

PAP: How did you design this trial?

M.W.: The study consists of two parts, each with two arms. In the first part, we want to check whether adding psilocybin - together with targeted psychotherapy - to standard pharmacotherapy improves the effectiveness of the treatment and whether it is safe. The second part of the study is designed to answer the question of how discontinuing an SSRI affects the effectiveness and safety of using psilocybin in drug-resistant depression.

PAP: Please tell us more about this compound, which we associate with hallucinogenic mushrooms.

P.M.: Psilocybin is classified as a so-called classic psychedelic, which acts mainly through serotonin receptors in the brain. This can manifest itself in a turbulent way, as a change in the state of consciousness, perception, thinking, emotions. All this can lead to very intense experiences, including mystical and spiritual ones.

PAP: A lot of research has been and is still being conducted around the world on the effects of psilocybin, as well as DMT, in patients suffering from depression. What is novel in your research?

M.W.: There are not that many clinical trials, i.e. those in which people with depression participate and the effect of psilocybin is directly assessed. To illustrate the scale - in the case of classic SSRI antidepressants, hundreds of such studies have been conducted, and in the case of psilocybin - a dozen or so. At this stage, basically every study using psilocybin in humans is innovative and can significantly expand our knowledge about the effects of psilocybin on the brain, and whether it can be used in treatment. In comparison to previous studies, ours stands out with a relatively large study group, as well as a planned assessment of the effect of the intensity of the psychedelic experience and parameters related to neuroplasticity on the therapeutic effect.

P.M.: In addition, it will be one of the first studies in the world to assess the effect of SSRI drugs on the effectiveness and tolerance of psilocybin in the treatment of depression. In previous studies, these drugs were discontinued before starting psilocybin therapy due to concerns about weakening the effect of psilocybin and increasing the severity of side effects. Recently, however, the first studies have appeared suggesting that such a combination is safe and effective. This is important because many patients, especially those with drug-resistant depression, take antidepressants for a long time and discontinuing them can be associated with a significant deterioration of their mental state. SSRI drugs, even if they are not fully effective, contribute to reducing the risk of suicide, among other things.

PAP: What makes psilocybin a potential candidate to alleviate or even cure depression?

P.M.: Psilocybin works at various levels in the brain. The mechanisms of its antidepressant activity include changes in receptor activity, synaptic plasticity, and functional connections in the brain. Studies have shown, for example, that psilocybin increases the density of connections between neurons in the hippocampus and prefrontal cortex. It supports neuroplasticity - the ability of the central nervous system to create new connections. Thanks to it, we can learn new things, develop new habits, and change existing habits and beliefs.

PAP: How important is the psychedelic effect of psilocybin here?

P.M.: This several-hour altered consciousness state can allow the patient to look at life and problems from a completely different perspective. A psychedelic experience can help make thought and emotional patterns more flexible, which results in greater openness and an increased level of self-acceptance. In addition, during such experiences, people often confront difficult emotions and memories. Thanks to the appropriate preparation of the patient and the support of an experienced psychotherapist, this process can bring relief and deep internal transformation.

PAP: Is there a 'hard' way to determine whether psilocybin treatment has worked, or will you have to rely on the subjective opinions of patients?

M.W.: Subjective effects, such as a sense of improvement in mental state and daily functioning, or a reduction in experienced suffering, are very important indicators of the effectiveness of our therapeutic activities, or its lack. Regardless of the 'hard' evidence, ultimately these are the main goals of treating depression. In our research project, however, we will assess not only the severity of depressive symptoms, but also the effect of psilocybin on biochemical and electroencephalographic indicators related to neuroplasticity.

PAP: How do you recruit patients for the study?

M.W.: We will probably recruit patients only in a year, after obtaining the approvals from both the EMA commission and the Chief Inspectorate. If we get the green light from these institutions, we will start recruiting patients. We will focus on the analysis of the treatment process to date, diagnostic evaluation and additional tests. During screening, it is crucial to exclude not only contraindications to participation in the study, but also other possible causes of drug resistance of depression, e.g. active addiction or somatic disorders.

PAP: After you select patients, what comes next?

M.W.: Each patient is randomly assigned to one of the study arms. Depending on the arm, they either take an SSRI and participate in standard psychotherapy, or receive psilocybin twice, with preparatory sessions before the first administration and integration sessions after each administration. Psychometric measurements and additional tests will be conducted in parallel.

PAP: How many such psilocybin sessions do you estimate will be needed to obtain satisfactory effects?

P.M.: Studies show that improvement in the mental state after one or two psilocybin administrations can last for 12 months. It may be a longer period, but we do not know that yet. Achieving a major change in life with a single or even repeated treatment would be a huge success. Therapeutic methods for drug-resistant depression other than oral pharmacotherapy, such as ketamine therapy or electroconvulsive therapy, most often require a series of treatments, booster treatments are also needed sometimes. In the case of psilocybin, perhaps a single session - in combination with psychotherapy - will be enough to contribute to a significant and long-term change in the patient's life.

PAP: Many people consider psychology a pseudoscience, despise psychotherapy sessions, believe only in chemistry.

P.M.: I understand this approach, but since we have been treating patients with drug-resistant depression for many years and use various innovative methods, we have been convinced that combining 'chemistry' with psychotherapy works much more effectively than taking medications alone. I am convinced that consuming hallucinogenic mushrooms alone will not cure anyone of depression. What a person does with the newly acquired neuroplasticity - whether they will implement changes in their daily life - is more important than the effect on serotonin receptors and the increase in the level of neurotrophic factors.

Interview by Mira Suchodolska (PAP)

mir/ bar/ mhr/ kap/

tr. RL