The Neuro Platform

If you’ve spent any time on TikTok lately, you’ve probably seen conversations around psychedelics blowing up. From celebrities openly discussing micro-dosing on their Instagram, to Netflix documentaries exploring plant medicine retreats, it feels like these substances are suddenly everywhere. At the centre of this is psilocybin, a chemical compound derived from certain types of mushrooms across the world. And yes, these are the same ‘magic mushrooms’ that have been the subject of stigma for many decades. Typically consumed dried or powdered, psilocybin belongs to a group of drugs called psychedelics, with these having the potential to alter a person’s sense of reality, leading them to experience the world in a completely different way (National Institute on Drug Abuse, 2024).

This isn’t really some new phenomenon though. There is evidence that indigenous people in Central America had been using these mushrooms for spiritual or healing rituals as far back as 3000 B.C (Carod-Artal, 2015). However, for decades, serious research was essentially off the table. But now? Now it’s being published in the leading journals and being funded by many, many universities, with researchers investigating psilocybin as a potential treatment for PTSD, depression and much more (Johnson and Griffiths, 2017).

So what’s changed, and what is actually going on inside the brain during a psychedelic experience?

What is Psilocybin and How Does it Work

When you ingest psilocybin, the body converts it into psilocin. From there, psilocin acts primarily as an agonist at serotonin receptors, specifically with the 5HT2A serotonin receptor. Under normal circumstances, serotonin receptors help to maintain the stable, predictable way we experience the world. However, under the influence of psilocin, these receptors are essentially flooded, and this throws the whole system into a state of unusual activity. This is what leads to the profound alterations in perception, emotion, and sense of self. What neuroscientists are now understanding is that these changes are not random, and they actually have massive implications for understanding and treating mental illnesses.

The REBUS Model

To understand the theory of how psilocybin works, let’s first think about predictive processing. The brain, according to this framework, is not a passive organ that just receives information from the outside world. Instead, it’s constantly generating predictions about what it expects to see, hear, and feel, only updating those predictions when something unexpected occurs (Corlett, Mohanty and MacDonald, 2020).

The problem is that in conditions like depression, the brain’s top-down predictions become so rigid that they override any incoming information from the world around us. A person with severe depression is trapped in a loop. The brain keeps predicting that things are hopeless, and filters every experience through that lens, regardless of what’s actually happening.

This is where the REBUS model comes in. Proposed by Professor Robin Carhart-Harris and the renowned neuroscientist Karl Friston (2019), REBUS stands for RElaxed Beliefs Under Psychedelics. Their model proposes that psilocybin works by relaxing the precision of those high-level, top-down predictions, and loosening the grip that mental patterns have over thought and perception. So, psilocybin create a brief window of plasticity in which rigid thought patterns, depressive loops, and trauma-linked associations become less fixed, and potentially, more open to change (Carhart-Harris and Friston, 2019).

The Structural Changes

Research has found that psilocybin also actively changes the brain’s structure. A single dose has been shown to induce rapid, sustained growth of dendritic spines in the frontal cortex, which heavily increases the communication between brain cells (Shao et al., 2021). These changes not only occurred super quickly, but were also persistent even a month later. These results show that psilocybin may have the ability to rebuild connectivity in brain regions that depression and other mental health disorders tend to erode.

This mechanism hasn’t yet been completely figured out, but appears to work through signalling cascades, including TrkB and mTOR, which are linked to being fundamental pathways for growth and neuroplasticity (Vargas et al., 2023). So, in other words, psilocybin appears to engage the pathways currently being used by the brain for growth and change, rather than simply overriding it.

The Challenges and Future Implications

However, even with the wealth of research backing psychedelic use in a medical setting, this isn’t a done deal, and there are many real challenges that are still unresolved.

A 6-month observational follow-up of the Carhart-Harris et al. (2021) psilocybin versus escitalopram (a selective serotonin reuptake inhibitor, widely used to treat depression) trial found that both groups showed sustained improvements in depressive symptoms at the 6-month mark, with no significant difference between them on the primary outcome measure. However, other studies have shown that the psilocybin group showed greater improvements in social functioning, psychological connectedness, and sense of meaning in life compared to those on escitalopram (Erritzoe et al., 2024). That said, even the authors caution that the study was underpowered to detect small but meaningful differences, had missing data, and relied on self-reported assessments, so these findings should be interpreted extremely carefully.

Research has also shown that this isn’t a treatment you can just prescribe and send someone home with. Participants in these trials received psychological support from specially trained therapists both during and around their dosing sessions (Goodwin et al., 2022). So, even though psilocybin may work to reduce the symptoms of depression, the model needs a lot of clinical infrastructure, and how that works within an already stretched NHS is a question that remains very much unanswered.

References

Carhart-Harris, R., Giribaldi, B., Watts, R., Baker-Jones, M., Murphy-Beiner, A., Murphy, R., Martell, J., Blemings, A., Erritzoe, D. and Nutt, D.J. (2021). Trial of Psilocybin versus Escitalopram for Depression. New England Journal of Medicine, 384(15), pp.1402–1411. doi: https://doi.org/10.1056/nejmoa2032994.

Carhart-Harris, R.L. and Friston, K.J. (2019). REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics. Pharmacological Reviews, 71(3), pp.316–344. doi: https://doi.org/10.1124/pr.118.017160.

Carod-Artal, F.J. (2015). Hallucinogenic drugs in pre-Columbian Mesoamerican cultures. Neurologia (Barcelona, Spain), [online] 30(1), pp.42–9. doi: https://doi.org/10.1016/j.nrl.2011.07.003.

Corlett, P.R., Mohanty, A. and MacDonald, A.W. (2020). What we think about when we think about predictive processing. Journal of Abnormal Psychology, 129(6), pp.529–533. doi: https://doi.org/10.1037/abn0000632.

Erritzoe, D., Barba, T., Greenway, K.T., Murphy, R., Martell, J., Giribaldi, B., Timmermann, C., Murphy-Beiner, A., Jones, M.B., Nutt, D., Weiss, B. and Carhart-Harris, R. (2024). Effect of psilocybin versus escitalopram on depression symptom severity in patients with moderate-to-severe major depressive disorder: observational 6-month follow-up of a phase 2, double-blind, randomised, controlled trial. eClinicalMedicine, 76(102799), p.102799. doi: https://doi.org/10.1016/j.eclinm.2024.102799.

Goodwin, G.M., Aaronson, S.T., Alvarez, O., Arden, P.C., Baker, A., Bennett, J.C., Bird, C., Blom, R.E., Brennan, C., Brusch, D., Burke, L., Campbell-Coker, K., Carhart-Harris, R., Cattell, J., Daniel, A., DeBattista, C., Dunlop, B.W., Eisen, K., Feifel, D. and Forbes, M. (2022). Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine, [online] 387(18), pp.1637–1648. doi: https://doi.org/10.1056/nejmoa2206443.

Johnson, M.W. and Griffiths, R.R. (2017). Potential Therapeutic Effects of Psilocybin. Neurotherapeutics, [online] 14(3), pp.734–740. doi: https://doi.org/10.1007/s13311-017-0542-y.

National Institute on Drug Abuse (2024). Psilocybin (Magic Mushrooms). [online] nida.nih.gov. Available at: https://nida.nih.gov/research-topics/psilocybin-magic-mushrooms.

Shao, L.-X., Liao, C., Gregg, I., Davoudian, P.A., Savalia, N.K., Delagarza, K. and Kwan, A.C. (2021). Psilocybin Induces Rapid and Persistent Growth of Dendritic Spines in Frontal Cortex In vivo. Neuron, 109(16). doi: https://doi.org/10.1016/j.neuron.2021.06.008.

Vargas, M.V., Dunlap, L.E., Dong, C., Carter, S.J., Tombari, R.J., Jami, S.A., Cameron, L.P., Patel, S.D., Hennessey, J.J., Saeger, H.N., McCorvy, J.D., Gray, J.A., Tian, L. and Olson, D.E. (2023). Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors. Science, 379(6633), pp.700–706. doi: https://doi.org/10.1126/science.adf0435.