What is psilocybin?

Psilocybin is a naturally-occurring molecule found in over 200 species of mushrooms

 
 

Psilocybin is a naturally-occurring molecule found in over 200 species of mushrooms, and it has the potential to revolutionise the way we treat depression. In 2018 it was granted “Breakthrough Therapy” status by the FDA.

It is structurally similar to serotonin – a neurotransmitter that regulates mood and perception.  Preliminary evidence by research groups around the world suggests that psilocybin treatments are more effective therapy than current strategies, and that their development should be fast-tracked.

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The UK has contributed a significant number of research studies on psilocybin to the world, and it has the potential to become a pioneer in developing psilocybin-assisted psychotherapy as a treatment for depression.

Unfortunately, psilocybin has been designated a Class A and Schedule 1 drug in the UK. This means that researchers now face enormous difficulties in studying its potential to treat depression, and have to spend prohibitive amounts of money and time in setting up clinical trials. Professor David Nutt, one of the UK’s leading psilocybin researchers, states that research involving psilocybin costs ten times as much as research on unprohibited substances.

What is the evidence?

Research institutes in both the US and UK have provided evidence that psilocybin could be a breakthrough treatment for depression, as well as OCD, cluster headache, and addiction.

Summary of evidencE

  • A single dose of psilocybin significantly reduced anxiety and depression in patients with terminal cancer, and this reduction lasted at least six months.

  • A single dose of psilocybin significantly reduced depression scores in patients with treatment-resistant depression, and this reduction lasted at least six months.

  • It is highly unusual for a medication to have such a profound effect on depression after only one treatment dose.

The first major study was performed with patients suffering from anxiety related to terminal cancer. Researchers at UCLA gave 12 patients with terminal cancer a dose of psilocybin, and on a different occasion a dose of a placebo (the patients did not know which was which). They found that the dose of psilocybin significantly reduced anxiety and depression scores (by the State-Trait Anxiety Inventory and the Beck Depression Inventory), and that these reductions were maintained over the course of six months (Grob et al, 2011).

In a later study at NYU School of Medicine, 29 patients with terminal cancer were given psilocybin, and on a different date a placebo (the order of which was randomised and unknown to the patients). The treatment was accompanied by several sessions of psychotherapy. They found that psilocybin, compared to placebo, greatly improved anxiety and depression scores (measured by the Hospital Anxiety and Depression Scale, Beck Depression Inventory, and State-Trait Anxiety Inventory). At the six-month follow-up, around 80% of the patients still had clinically significant reductions in depression (Ross et al, 2016).

At around the same time, a team at Johns Hopkins University carried out a similar study on 51 terminal patients, giving patients psilocybin in the presence of trained guardians. This study also found significant decreases in anxiety and depression scores (measured by the Hamilton Depression Rating Scale, Hospital Anxiety and Depression Scale, Beck Depression Inventory, and State-Trait Anxiety Inventory), and reported that around 80% of participants still had clinically significant improvements after six months (Griffiths et al, 2016).

In these three studies, the therapeutic benefits of psilocybin were remarkable. Typical treatments of depression require many months of medication or therapy, and only have a positive effect in around half of patients. In these studies, a single dose of psilocybin was having benefits for over six months, and over 70% of patients were in full remission at the end of the studies.

Concurrently, Imperial College London’s research group led by Dr Carhart-Harris and Professor Nutt administered psilocybin to 12 patients with treatment-resistant depression. Non-intensive psychological support was offered before, during, and after a low dose and high dose session for each patient. They found that the treatment significantly reduced depression scores (measured by the Quick Inventory of Depressive Symptoms and Beck Depression Inventory), with two thirds of patients in remission one week after the treatment (Carhart-Harris et al, 2016). 

A six month follow-up showed depressive symptoms were still reduced, even without ongoing psychological intervention from the investigators (Carhart-Harris et al, 2018).

How does psilocybin work?

Research taking place internationally is beginning to paint a clearer picture of how psilocybin acts on the brain. 

Psilocybin is structurally similar to serotonin, which is a neurotransmitter that regulates things like mood, sleep, and appetite. 

Psilocybin binds to serotonin receptors in the brain, and the one that it likes the most is the 5-HT2A receptor.

Activation of this receptor causes a large number of changes in the brain, altering mood and perception in significant ways. Recent neuroimaging studies have shown that psilocybin temporarily increases the entropy of the brain; which means it allows the brain to become more flexible and make connections it wouldn’t normally make (Carhart-Harris et al, 2017). 

An image from Petri et al. (2014) showing the difference in brain connectivity between a normal brain (left) and the brain of a person who has been given psilocybin (right). This does not mean that the brain is working harder with psilocybin, but means that the brain makes a greater number of unusual connections.

An image from Petri et al. (2014) showing the difference in brain connectivity between a normal brain (left) and the brain of a person who has been given psilocybin (right). This does not mean that the brain is working harder with psilocybin, but means that the brain makes a greater number of unusual connections.

According to one theory, this temporary increase in brain entropy places the brain into a state that allows for “active coping” – helping the brain fundamentally restructure itself to break free of a depressive state. This is compared to the “passive coping” achieved by many antidepressants (that activate the 5-HT1A receptor), that may only serve to dampen the symptoms (Carhart-Harris & Nutt, 2017).

Additionally, psilocybin has been shown to have an effect on the way people process emotions. One study showed that psilocybin reduced the activity in the amygdala, one of the brain’s core emotion-processing hubs, in healthy volunteers. The participants showed improvements in mood, and reacted less negatively to images of unhappy or angry faces. It’s possible that this effect of psilocybin could help depressed patients process negative emotions in less harmful ways (Kraehenmann et al, 2014).

These two effects of psilocybin could be the reason why patients see such significant improvements in symptoms of depression after a single dose. 

Is psilocybin safe?

Psilocybin is a safe molecule. There have been no credible reports of deaths from psilocybin toxicity, and we know that it is broken down quickly in the body and has no physiological side effects. It is not addictive, and does not cause long-term tolerance or dependence (Tyls et al, 2014).

The potential risks of psilocybin use are due to its profound effects on perception. If patients are not cared for correctly, they may experience lapses in judgement that could lead to unsafe behaviours. This is why psilocybin treatment should always be performed under a trained monitor, clinician, or therapist.

What would psilocybin treatment look like? 

Psilocybin can substitute or work alongside existing antidepressant treatments.

Although the protocol of psilocybin treatment varies among institutions and researchers, participants are always under constant supervision, and a medical specialist is always present. Participants are kept in a safe, comfortable environment, often with music provided. Someone is always present in the room to provide either non-intrusive guidance, or sometimes more focussed psychotherapy.

It appears that a therapist is not required for a dose of psilocybin to have a significant antidepressant effect, and in some studies only trained monitors are present. Their role was simply to provide reassurance or guidance if the participant became distressed.

According to the ‘bipartite’ model of depression, many patients could potentially benefit from a combination of contemporary antidepressants and occasional high-dose psilocybin sessions (Carhart-Harris & Nutt, 2017). This means that psilocybin treatment would not necessarily require a significant shift in current treatment regimens, and would be of relatively low cost to the NHS due to its infrequent nature (benefits from one session seem to last over six months in most patients).

What needs to happen next?

To see this kind of psilocybin therapy become reality, we need to remove the restrictions on researchers that are preventing clinical trials from taking place. Psilocybin must be rescheduled to allow UK scientists to begin larger investigations into its powerful antidepressant effects.

The evidence shows that psilocybin is a safe molecule with very low potential for abuse and its prohibited status is inconsistent with its risk factor. If the UK changes its laws to allow for freedom of research, it could propel a breakthrough in mental healthcare and put the UK at the forefront of a growing academic field and industry.

References

Carhart-Harris & Nutt (2017) Serotonin and Brain Function: A Tale of Two Receptors. J Psychopharm, 31(9), p1091-1120.

Carhart-Harris et al. (2016) Psilocybin with Psychological Support for Treatment-Resistant Depression: An Open-Label Feasibility Study. Lancet Psychiatry, DOI: 10.1016/ S2215-0366(16)30065-7

Carhart-Harris et al. (2017) Psilocybin for Treatment-Resistant Depression: fMRI-Measured Brain Mechanisms. Scientific Reports, DOI: 10.1038/s41598-017-13282-7

Carhart-Harris et al. (2018) Psilocybin with Psychological Support for Treatment-Resistant Depression: Six-Month Follow-Up. Psychopharmacology, 235, p399-408.

Griffiths et al. (2016) Psilocybin Produces Substantial and Sustained Decreases in Depression and Anxiety in Patients With Life-Threatening Cancer: A Randomized Double-Blind Trial. Journal of Psychopharmacology, 30(12), p1181-1197.

Grob et al. (2011) Pilot Study of Psilocybin Treatment for Anxiety in Patients with Advanced-Stage Cancer. Arch Gen Psychiatry, 68(1), p71-78.

Kraehenmann et al. (2014) Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with Enhanced Positive Mode in Healthy Volunteers. Biological Psychiatry, DOI: 10.1016/j.biopsych.2014.04.010

Petri et al. (2014) Homological Scaffolds of Brain Functional Networks. J. R. Soc. Interface, DOI: 10.1098/rsif.2014.0873

Ross et al. (2016) Rapid and Sustained Symptom Reduction Following Psilocybin Treatment for Anxiety and Depression in Patients with Life-Threatening Cancer: A Randomized Controlled Trial. Journal of Psychopharmacology, 30(12), p1165-1180.

Tyls et al. (2014) Psilocybin - Summary of Knowledge and New Perspectives. European Neuropsychopharmacology, 24, p342-356.