Magic mushrooms and depression

Screenshot 2021-04-16 at 11.28.56Depending upon where you get your news, you may have seen reports that the active ingredient of magic mushrooms, psilocybin, is being studied as a possible treatment for depression.

Being of a certain age, I remember the 1960s and 70s when magic mushrooms were all the rage. The law at the time was ambiguous in that picking the mushrooms wasn’t illegal but extracting psilocybin was. There were reports of people exploiting the loophole by crawling on all fours to graze directly on the mushrooms. A somewhat risky business, as those people were perhaps not the best at distinguishing psilocybin species from those far more toxic. But back to the topic of this blog post – what’s the link between psilocybin and antidepressants?

Sometimes dismissed with a “pull yourself together,” in reality depression is as real a condition as any biochemical disorder from diabetes to Gaucher disease. By far the most commonly prescribed antidepressants today are the Selective Serotonin Receptor Uptake Inhibitors or SSRIs. An early SSRI was fluoxetine, better known as Prozac, which is still widely used*. Although an effective drug, it’s not without some controversy as its development was based on what’s known as the serotonin hypothesis of depression. Serotonin is a hormone which interacts with receptors in the brain. There are 15 known receptors, with 5-HT1A and 5-HT1B being the most extensively studied (5-HT stands for 5-hydroxytryptamine – the chemical name for serotonin). Serotonin receptors are proteins which when bound to serotonin, mediate the release of a range of neurotransmitters such as dopamine (amongst others). Serotonin is transported across the brain and its concentration partly depends on re-uptake by nerve cells. Inhibiting re-uptake by a SSRI results in higher concentrations of serotonin outside the cells and hence, so the theory goes, there’s more available to bind onto the 5-HT receptors.

The serotonin hypothesis of depression is controversial because the biochemistry of serotonin interactions is complex and not fully understood. There may also be genetic aspects, particularly in sub-types of proteins involved in serotonin transport (known in genetic-pharmacology jargon as polymorphisms). Moreover, evidence of an association between higher levels of serotonin in the brain and depression is not compelling. Even though the pharmacological mechanism isn’t well understood, SSRIs are effective in clinical trials and so they clearly have some influence on all this intricate biochemistry.

Interestedly, psilocybin also acts on 5-HT receptors, 5-HT2A in particular. To be more precise, psilocybin contains a phosphate group on its molecular structure, making it pharmacologically inactive. The phosphate group is removed either by stomach acid or in the bloodstream to form psilocin which is the active substance. It crosses into the brain and reacts with a variety of receptors, including the 5-HTs. It leads to complex reactions in cellular signalling, resulting in cascade effects which ultimately cause alterations to sensory perception. Apart from 5-HT receptors, how psilocybin might affect depression is not understood but, like SSRIs, there appears, perhaps, to be an effect in clinical trials. Now is the time to be very cautious because the clinical trials have so far been very preliminary. The first trial appears to be in 2016, conducted at the Centre for Psychedelic Research at Imperial College, London, with a more recent study this year. The number of participants was small, 59 in the 2016 study and 80 in this years. Other institutions have likewise been studying the effects of psilocybin on depression and Imperial have also been looking at its use to treat Anorexia nervosa. In addition, some imaging studies have been performed using functional-MRI (fMRI) but so far, no extensive trials have taken place.

If psilocybin and its related compounds are eventually developed to treat depression, then I suspect the chemical structure will be modified in an attempt to optimise it’s effectiveness and reduce side effects. I also suspect that the choice of dosages will be challenging. Nevertheless, an interesting area of pharmacology might be on the rise – we will wait and see.

* – Stanley Feldman’s From Poison Arrows to Prozac (how deadly toxins changed our lives forever) tells the fascinating story.

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