Magic mushrooms against depression — is the hype justified?

Recently, Atai Life Science, a biotech start-up, caused a sensation with its IPO (=initial public offering). The special thing about it — the German-based company is looking for alternative therapy methods to treat mental illnesses such as depression, anxiety and addiction disorders or personality disorders. In recent years, one active ingredient in particular has become the focus of public interest — psilocybin. This is present in fungi such as psilocybe (bald heads, see picture; hence the name). Psilocybin is said to have an intoxicating effect, which is why these mushrooms are mainly known in the drug scene. Furthermore, psilocybin leads to gastrointestinal symptoms (e.g. vomiting, diarrhoea), hallucinations (e.g. visual) or flashbacks. Important: Mushrooms do not cause physical or psychological dependence or withdrawal symptoms (European Monitoring Centre for Drugs and Drug Addiction, 2006), but lead to tolerance formation when taken regularly (one needs an increasingly larger dose to achieve the same effect). The ingestion of mushrooms containing psilocybin is by no means a phenomenon of modern times — such mushrooms were consumed for festivities as early as 1000 BC, especially in Latin America. However, more systematic investigations did not take place until the 20th century, which eventually led to the development of the term “magic mushrooms” (Gordon Wasson, 1957). Since then, there have been numerous individual case reports and smaller studies dealing with the effect of psilocybin on psychiatric diseases. Using depression as an example, I would like to show here whether it might be worthwhile to use hallucinogenic mushrooms for therapy.

A psilocybe mushroom (source: nature.com)

Psilocybin belongs to the so-called psychedelic drugs — hallucinogenic, psychotropic substances. LSD, ecstasy (especially MDMA) also belong to this class. In Switzerland, the use of psychotropic substances (and thus also hallucinogens such as psilobycin) is regulated by the Narcotics Act. It states that “the following narcotics [note: including hallucinogens] may not be cultivated, imported, manufactured or placed on the market.” A violation of the Narcotics Act is punishable by a fine up to a three-year prison sentence. Research, on the other hand, has long been possible with an exceptional permit from the Federal Office of Public Health (FOPH) and has a long tradition in Switzerland.

Current research results
Over the last 5–10 years, the number of studies investigating the effect of psilocybin on depressive symptoms has been steadily increasing — with mixed results. Here are a few recent examples:

  • Carhart-Harris et al. (2021): In a so-called randomised controlled trial (=highest quality form of a clinical trial), which examined the effect of psilocybin and one of the most common antidepressants, escitalopram, there was no significant difference between these two substances.
    Limitations: short study duration (6 weeks), patients were not of different ethnic origin, which makes generalisation impossible, potential conflict of interest (authors’ funding).
Figure 1. (Calvao-Goelho, 2020) Effect size (SMD) of acute, medium-term and long-term clinical effects of classical serotonergic psychedelics vs. placebo treatments on depressive symptoms of patients with mood disorders (P), presented as Hedges’ g with 95% confidence interval. A negative Hedges’ g is in favour of psychedelics. For your information: if the so-called p-value (p) is <0.05 and/or the 95% confidence interval (interval between t-CI and u-CI -> the respective left and right end of the line/rhombus) does NOT contain the value 0, then the difference can be considered statistically significant! Underneath you see the combined value (tendency across all studies), which seems to be statistically significant in favour of psychedelics.
  • Goldberg et al. (2020): In another meta-analysis, psilocybin was shown to significantly reduce symptoms of anxiety and depression.
    Limitations: Blinding (i.e. patients and physicians do not know whether the patient received the placebo or psilocybin) was not possible due to the characteristics of psilocybin ingestion. Further: small number of included studies, reduced ethnic diversity and so-called selection bias (=statistical bias in the selection of patients; e.g. only certain patient collectives engage in this study), potential conflict of interest of the study authors (receipt of funding support from industry).

So — enough about clinical studies and statistical analyses. I have deliberately included only those studies which, according to the state of the art, have the greatest evidence (=conclusiveness). I also searched for these studies in the PubMed study pool — the largest online database of medical studies. This includes randomised controlled trials and meta-analyses. Personally, I am ambivalent about the results. Psilocybin seems to be at least as effective as placebo and other antidepressants. BUT: the studies have certain limitations, especially concerning the study size, the selection of the patient population (“selection bias”), lack of blinding, the different assessment scales and psilocybin doses. In my opinion, further research, especially with standardised research protocols (definition of dose and placebo) and larger studies, is absolutely necessary to conclusively assess the efficacy of psilocybin. This is also against the background that psilocybin can also have side effects such as headaches, nausea or fatigue. Other physical effects include breathing difficulties, palpitations, altered blood pressure, circulatory problems, an increase in body temperature, sweating, loss of balance, dizziness, and more rarely fainting and epileptic seizures. Side effects were comparable to those of escitalopram in the study by Carhart-Harris (2021, see Figure 2).

Figure 2. (Carhart-Harris, 2021)

One problem in research on the treatment of depression is certainly the large variety of potential antidepressants. Not every antidepressant works equally well in every patient, and often it has to be changed several times until there is an improvement, which makes it difficult to compare with psilocybin. I can confirm this: I am now on my 4th (!) antidepressant, as the previous three either did not work (due to genetics, among other things) or led to major side effects. For me personally, the data on psilocybin and depression is still too thin to get involved with it in good conscience. In addition, psychotropic substances can also intensify existing symptoms such as hallucinations or dissociations, which would not be very beneficial in my case. Therefore, I strongly advise against independent (without seeking medical advice) consumption of these psilocybin-containing mushrooms — especially if you have a pre-existing psychiatric or physical condition. (apart from the fact that it is still illegal) In principle, however, I am of the opinion that these alternative therapy methods should also be tested — but this should be done in a scientific-objective way and, if possible, without industry funding. For example, cannabis has been shown to have a positive effect on reducing pain in cancer patients (more on this later). I am curious to see what the future will bring — I will keep you up to date!

— Tim

Mental and Public Health Enthusiast, Student Research Assistant and DID Patient