When Lia is unwell, she stays in bed and withdraws from the outside world. She doesn't respond to messages or calls. She doesn't have any strength. "Depression is a kind of gray cloud that takes over my brain," says Lia.
Klaus describes his depression as indifference and being separated from his own feelings: "the worst thing was no longer being able to feel life. Just functioning."
Lia and Klaus are test subjects in the EPIsoDE-study. Their depression is considered to be treatment-resistant. This means the conventional psychopharmaceuticals barely work on them. They are two of a total of 144 test subjects in the largest study on the efficacy and safety of psilocybin in the treatment of depression in Germany. The study is being conducted by CIMH together with Charité in Berlin and the charitable organization MIND Foundation and is sponsored by the Federal Ministry of Education and Research. The investigation is looking at whether and if so how much the administration of psilocybin in combination with psychotherapy helps in patients with treatment-resistant depression.
"Psilocybin is a substance with a psychedelic mechanism of action that is found in some types of mushrooms. Our investigations aim to show whether psilocybin has a better antidepressant effect than a placebo. At the same time, we are also recording the possible risks of the treatment for our patients," explains the head of the study, Prof. Dr. Gerhard Gründer, who heads up the Department of Molecular Neuroimaging at CIMH.
Are psychedelics the solution?
Psychedelics or hallucinogens are substances that change consciousness, perception, and the emotional experience. They enable new experiences to be had and set change processes in motion. They have been used for millennia in indigenous healing systems for shamanic rituals: DMT in ayahuasca, mescaline in the peyote cactus, and mushrooms containing psilocybin. Psychedelics can ensure that old patterns of thinking and behaving are broken. This makes them interesting for the treatment of mental illnesses. They don't just change our subjective experience, they also impact our brains. Links between nerve cells that recede in patients with depression can form new structures again as a result of psychedelic substances.
Dr. Andrea Jungaberle, co-founder of MIND Foundation and part of the study team at Charité in Berlin, compares this process to a snow globe that is swirling around: "psychedelics have the ability to shake things up. That's the reason why they work so wonderfully well." The particles that swirl around in the snow globe suddenly land in an entirely different place than they were before. Entirely new thoughts and perspectives open up after an experience with psychedelics. Instead of remedying a defect in the brain like medications, psilocybin aims to change the perspective on what is already there.
Not everyone has a positive experience. Hallucinations can also trigger anxieties or bring things that have long been suppressed by the consciousness back to the surface. "Lots of patients find themselves to be emotionally open, more sensitive, and in contact with their deep emotional wounds before and after a psychedelic experience. It can be very painful," explains Lea Mertens, study coordinator and study therapist at CIMH. Lots of people are scared of having a psychedelic experience as a result. In reality, respect is appropriate, Gründer explains. "But you don't need to worry, if fear occurs during the experience, that might be something that is ultimately very helpful." Mertens adds "like in regular psychotherapy, the key to processing lies in confronting your own fears and dealing with difficult experiences." Gründer and Mertens agree that therapeutic and medical support is important to the efficacy and also the safety of this therapy.
Psychedelics in research
The fact that psychedelics such as psilocybin or LSD have a special effect in the brain and can alleviate psychological problems is nothing new. Back in the 1950s and 1960s psychedelics were tested on around 40,000 patients around the world, and there were promising results. The studies showed an improvement in the symptoms of depression in the majority of those affected. They were also already being used in alcoholics and those with end-stage cancer.
Psychedelics, though, were also becoming ever more popular as a party drug at the time. The hippie movement discovered them for themselves to leave the bourgeois world and its conventions behind them. Negative headlines about the downsides of psychedelics pushed them further into focus. In the late 1960s, this development was suddenly stopped: all classic psychedelics, from psilocybin to LSD, were banned, initially in the US and then around the world. Their consumption moved underground, and research in this field ground to a halt. Promising approaches were put on ice, and psychedelics were banned from the teaching materials as far as possible. Only since the 2000s have they been the focus of psychopharmacological research once again. The renaissance of the psychedelics is in full swing. The safety and efficacy of the substances are being tested for the first time in modern clinical studies.
Previous pilot studies on psilocybin indicate that the substance is safe and well tolerated if personal risk factors are excluded and they are administered in a controlled, therapeutic setting. The EPIsoDE-study is now investigating this potential in greater detail and is therefore one of the largest studies of this type.
The EPIsoDE-Study
A total of 144 test subjects with treatment-resistant depression between the ages of 25 and 65 are taking part in the EPIsoDE-study (Efficacy and safety of psilocybin in treatment-resistant major depression), which launched in 2021. They are all receiving two six-hour to eight-hour substance sessions at an interval of six weeks. Under therapeutic supervision, they either receive a high dose of the active substance psilocybin, a low dose, or a placebo preparation. The study is designed in such a way that all test subjects are guaranteed to receive a high dose in one of the two sessions. The participants will receive therapeutic support for three months to process the experiences. This includes preparatory sessions and integration sessions in which the experiences are embedded in a personal framework. There are then follow-up tests to determine the long-term effect.
The intensive moments that test subjects experience in a session of this type are also a special experience for the therapist supporting them. Study leader and therapist Gründer says "it's not just the most important study I've ever done, it's also the most moving. What we experience in the treatment room with the patient are the most moving experiences of my professional career for me as a therapist."
The study will likely be completed in late 2023, with the final results expected in early 2024. "There's still a while to go before possible approval of this therapy in Germany and the rest of Europe. We still need more, even larger, multicenter, phase 3 studies with positive results. We are also working intensively on the issue of the reimbursement of costs by the statutory health insurance providers, and this is being included in the planning of additional studies," explains Gründer.
A mystic experience?
The sessions changed something in test subject Lia. "Before the sessions I didn't have the same access to myself that I experienced yesterday. It was as if there were no more blockages between me and myself," she said after her first experience with psilocybin. For Klaus, it goes even further: "it's the most life-changing experience I've ever had."
After a psychedelic experience, lots of people report a feeling of connection to everything or encounters with other creatures. These people feel like they cannot hold on to their experience or express it in words. People also talk about a mystical experience, an experience that exceeds everything previously experienced. Some participants in the EPIsoDE-study also describe experiences of this type and are overwhelmed, but this is by far not everyone. While some seemed to gain an entirely new perspective on their existence, almost nothing happened to others.
The duration of effect afterwards also varies significantly between individuals, from no change at all up to half a year or longer of freedom from symptoms. One difficulty that the test subjects experience is integrating what they have experienced into everyday life. The factors that ultimately dictate how long-lasting psychedelic treatment is in individual cases are still entirely unclear. This can only be addressed in greater detail through further studies. One thing is for sure, though, all of the problems don't just simply disappear overnight with a psychedelic experience. The experience opens a door and may be the start of a change.
View of the future
How will the reintroduction of psilocybin change research into and the treatment of depression? Gründer thinks it will be huge: "I think that it's the start of a paradigm shift in psychiatry." In the past, mental illnesses have often been linked to a malfunction of the brain that can only be treated by long-term treatment with medication, but studies with psilocybin show that a long-lasting improvement in symptoms of the disease can occur after just a single session. The EPIsoDE-study could therefore not just contribute to the development of a new treatment method, but also to our understanding of mental illnesses and psychological experiences.
There are still many unanswered questions that need to be addressed in other studies. What will change if the substance is administered more frequently? How does psilocybin work over a longer period? How can the substance sessions best be linked with psychotherapy? This is the only way to ensure reliable and safe therapy.
Although social interest is constantly increasing and the expectations are huge, further patience is needed along with clarification about the possibilities and limits of the substance. Yes, psilocybin has the potential to help a lot of people, but psilocybin is not a universal remedy and comes with risks. The EPIsoDE-study team is aiming to create a perspective of psychedelics beyond the fear and the hype.