Can psilocybin mushrooms have any medicinal value?

Magic mushrooms on prescription? : Hallucinogenic drug is said to relieve depression in the long term

A gray veil seems to lie over everything, the body is leaden, exhausted and listless and worn down by sleepless nights. The thoughts circle in endless downward spirals. Life appears empty, meaningless and lost. This is what depression feels like.

More than 322 million people worldwide suffer from this insidious, sometimes fatal mental illness, in Germany alone there are over five million. Conventional therapies do not work or no longer work in around half of them - they suffer from what is known as treatment-resistant depression.

Therefore, researchers have long been looking for new approaches to treat this steadily growing group of patients. One option could be psilocybin, an ingredient made from psychoactive mushrooms, also known as “magic mushrooms”, which can cause hallucinations and euphoria, among other things. The idea behind using the substance, which was previously only known as a drug, as a therapy is: The active ingredient should lead to a kind of "reset" in the brain and could thus positively change the consciousness of people with severe depression in the long term.

There are now some indications that this can work. A study at Johns Hopkins University (JHU) in Baltimore in 2016 showed that treatment with psilocybin and accompanying psychotherapy could significantly reduce the fear of death and depression in cancer patients. In London, too, doctors at Imperial College were able to help twelve patients with therapy-resistant depression with only two doses of psilocybin a few days apart. In all patients, symptoms resolved for at least three weeks after treatment. In five of them, the effect lasted for up to three months.

"The magnitude of the effect that we saw was about four times greater than what clinical studies for traditional antidepressants have shown on the market," said Alan Davis of JHU recently on the occasion of a follow-up study.

Psilocybin is recognized as a Breakthrough Therapy

There are reasons why the effect of the well-known psilocybin is only now being recognized. For years, the field of research around psychedelics lay idle, because psilocybin and other hallucinogenic substances, including LSD, have been subject to the provisions of the Narcotics Act (formerly known as the “Opium Act”) since the 1960s. This had little effect on recreational consumption, but research and therapeutic use hindered this considerably.

Then two years ago the tide turned. Psilocybin has been recognized by the US FDA as a "Breakthrough Therapy" for severe depression in order to accelerate the development and regulatory review of the active ingredient - also in Germany.

"In recent years there have been repeated attempts by individual German researchers to initiate smaller studies with small groups of test subjects," says Gerhard Gründer, from the Central Institute for Mental Health in Mannheim. But that always failed at the Federal Institute for Drugs and Medical Devices (BfArM). "Germany, the German authorities and the scientific community were - and in a sense still are - very conservative when it comes to psychedelics," says the researcher.

That is changing now. In collaboration with a research group from Charité Berlin and the MIND Foundation, Gründer is preparing a study to examine the effects of psilocybin-supported treatment in patients with therapy-resistant depression. Last week he and his team received final approval from the BfArM.

It is scheduled to start next March. It is a phase II study with a total of 144 patients: the world's second largest psilocybin study, only surpassed by the British company Compass Pathways, which is currently doing research on just over 200 patients. “There has never been a project like this in Germany,” says founder. "With this major project, we hope to finally catch up with the top researchers in the field of psychedelics in Switzerland, the USA and Great Britain."

The study will cost 3.8 million euros, 2.2 million euros will be borne by the Federal Ministry of Education and Research (BMBF). Under medical supervision, three different dosages of psilocybin - high, low and placebo - are to be tested against each other. "Based on the data available so far, I assume that we will observe a strong antidepressant effect in the group that receives a high dose of 25 milligrams," says Michael Koslowski, psychiatrist and member of the research group at the Charité in Berlin.

At the low dose of five milligrams, however, one suspects only weak psychedelic effects. After six weeks, the process should be repeated so that the patients who received only a low dose or a placebo in the first round also have the chance to experience a “potentially mind-altering trip” and, as a result, to be able to overcome their depression.

The trip itself has therapeutic value

Founder does not believe that psilocybin only works by changing the nerves in the brain, but that the "trip" itself is important for the therapy. "There are good reasons to think that the psychedelic experience plays a major role in the anti-depressive effect," he says. "I don't think that substances that have a similar neurobiological effect but have no psychedelic effect can be equally effective, but that remains to be seen".

A psilocybin trip usually begins with a tingling sensation in the arms and legs, many then suddenly have to laugh, a feeling of warmth sets in. Depending on the dose, psilocybin can also trigger intense changes in perception - such as hallucinations or synaesthetic experiences, in which one believes to perceive the taste of a noise. Often reports of a loss of sense of time as well as changes in emotions and thoughts or a dream-like experience of reality are reported. Psilocybin is also said to trigger a feeling of strong connection with other people and nature.

Psilocybin is not considered to be addictive and there is no known long-term physical harm, but there are certain risks and side effects associated with its consumption. The unpleasant physical effects include breathing difficulties, rapid heartbeat, sweating, headaches, dizziness and nausea. High doses in particular can also trigger fear, visions of horror and even delusions.

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However, the founder sees such “horror trips”, at least in the therapeutic setting, “not that critical”. It might sound contradictory to let depressed people of all things go through such a fear-filled experience, but "this can then be used well in the psychotherapeutic process".

In people with cases of schizophrenia or manic depression in the family, however, the risk of having a seriously negative reaction to the drug is significantly greater - in the worst case, a psychotic episode with a complete loss of sense of reality could result. Therefore, "patients with a history of psychosis or a first-degree relative from psilocybin studies are always excluded," says founder.

It acts like a "reset" in the brain

But is it justifiable to administer potentially harmful substances to mentally ill, vulnerable people? "Therapy with medication is always a risk-benefit assessment," says founder. He is convinced that the potential benefits of psilocybin far outweigh the risks. "It is a real opportunity to develop further in psychiatry and to be able to open up a new therapy option for large patient groups."

However, the research is still at the beginning. How exactly and why psilocybin appears to be effective against depression in the long term is unclear, says Michael Koslowski. But there are already first explanations. Psilocybin initially appears to dim the amygdala, the fear center in the brain that is often hyperactive in depressed people. This is what researchers from Imperial College London observed when they gave the active ingredient to patients with depression in 2017 and tracked their brain activity in the magnetic resonance tomograph.

In addition, it seems to have a positive influence on the connection between the nerve cells in the brain. "Translated to the psychological level, this means that old, hardened ways of thinking and behavioral structures dissolve, creating space for new connections," says Michael Koslowski. “In very simplified terms, one speaks of a 'reset' mechanism”, a kind of restart like a computer.

[Do you, a relative or a friend have symptoms of depression or even thoughts of suicide? You can find help at the free telephone counseling on 0800 1110111, the Berlin crisis service on 39063-10, -20 etc. to -90, or here.]

This could also be why psilocybin has been shown to be effective for other mental disorders, such as addictive behavior, anxiety, and eating disorders. What connects these diseases with one another is a subjective as well as neurological hardening of certain thought patterns. “These substances, and the psychedelic experience they bring with them, create a certain flexibility that can be used psychotherapeutically,” says Koslowski.

Approval as a drug before this decade

In view of the predominantly positive study results so far, Koslowski warns of the insidious "expectation effect" of clinical studies and new therapies. That means that at the beginning there is often a lot of euphoria about the wide range of treatment options for a new active ingredient. However, this could lead to misinformation and therapies being prematurely disseminated, which later turn out to be not so optimal. Effect sizes can also be artificially inflated by small groups of test persons, which leads to the effectiveness of a treatment being overestimated.

Koslowski emphasizes that the evidence for psilocybin is still "relatively thin". So far, control data are also missing in many of the studies, as it is particularly difficult to find a placebo that convincingly mimics the hallucinogenic effects of psilocybin. This means that the patient and the doctor know whether the placebo or the active ingredient has been administered - “blinded” studies are therefore not possible. Still, Founder hopes to get psilocybin approved later this decade. For a much-needed new drug for depression.

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