What is Psilocybin and How Could it Help Depression?

bizjarvis
2 days ago
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OpenMind Educational Preface

This original educational article was written by Isobel Jarvis for the OpenMind Initiative Education Hub. It provides a comprehensive exploration of the neurobiology of depression, the historical and scientific limitations of the monoamine deficiency hypothesis, and the therapeutic mechanisms through which psilocybin promotes rapid neuroplasticity and default-mode network recalibration. The content is presented unaltered as authored, and is intended for educational purposes.

Introduction & The Pervasive Scale of Depression

Since the late 90s psilocybin has been showing promising results in the field of depression treatment. However, despite its success, it has faced controversy. In this article I aim to explain the key mechanisms behind depression and psilocybin’s ability to counteract it. I will also shed light onto why researchers are looking into alternative treatments despite various forms of therapy already existing in mainstream healthcare.

Affecting approximately 5.7% of the population, depression is one of the most common mental illnesses (WHO, 2025). While exact statistics are difficult to confirm, it’s known that depression has a pervasive effect on society, costing people money and quality of life. Depression can have a variety of origins and present in different forms. The most common is Major Depressive Disorder (MDD), but depression’s range spans from Post-Partum Depression to Seasonal Affective Disorder to Bipolar Disorder. It is an illness that not only disrupts people’s personal lives but also, more widely, the economy: in the US alone (a population of approximately 330 million), MDD’s total economic burden stands at $326.2 billion, due largely to lost working hours (Greenberg et al., 2021).

Delving into the Depressed Brain: mPFC & The Amygdala

If we delve into what exactly happens in the depressed brain, we can start to understand why the cognitive patterns surrounding depression exist. In MDD, there is a significant increase in activity in the medial prefrontal cortex (mPFC) – a region strongly involved in self-referential thinking. Rolls et al. (2020) found that hyperactivity in the mPFC was associated with increased negative processing of emotions and a heightened memory of negative emotions. In addition, increased activity was observed in the amygdala – a region in the limbic system that has a key role in fear and negative emotional responses. The amygdala also connects directly to the orbitofrontal cortex (OFC) (another region found to show increased activity in MDD). The OFC is a region which plays a role in connecting emotion and memory to produce an evaluation of a stimulus (Rolls, 2019).

The disorder commonly entails an increased dwelling on the negative and a perceived inability to see or strive for the positive. These findings appear to correlate with this experience. Most significantly Pellegrini et al. (2021) found that MDD patients had significantly reduced perceived life enjoyment compared to controls and that this correlated with increased activity in sections of the OFC.

Hypofunction & The Loss of Top-Down Regulation

While some sections of the brain are found to increase in activity, others are found to decrease. For example, Krystal et al. (2020) discuss how some areas of the prefrontal cortex are found to decrease in activity, and hypothesise that the loss of prefrontal cortical neurons could be responsible for a loss of this function.

The outcome of these alterations in activity level is that the reactive, ‘lower down’ regions in the brain relating to processing negative emotions increase, while some of the functions of the cortex that ‘hold back’ these responses decrease. This is known as a loss of ‘top-down’ regulation. Top-down regulation is the process of the cortex regulating emotional reactions and responses. It can be likened to a border control – normally it controls the influx and stops the brain from being flooded, but in MDD this control weakens and the unregulated flood of negative emotions can take over.

What’s Wrong with Current Methods of Treatment?

So, what’s wrong with our current methods of treatment? Well, current medications (SSRIs, NSRIs, etc.) are designed based on a theory known as the Monoamine Deficiency Hypothesis (MDH) – the idea that depression is caused by an underactivity of monoamine neurotransmitters (dopamine, noradrenaline, serotonin). The discovery that drugs which increase monoamine activity appeared to improve depressive symptoms gave rise to this hypothesis and became the main theory for depression treatment and has greatly influenced where drug-research money is spent.

Recent reviews have debunked the consensus that depression is caused simply by underactivity of serotonin, although this idea continues to be used in clinical practice. Most prominently, Moncrieff et al. (2022) found ‘no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations’. This is of significant concern given that the most commonly prescribed antidepressants – SSRIs – operate on the basis that serotonin is deficient. If the monoamine deficiency hypothesis is not a reliable explanation for depression, this would call into question the relevance and efficacy of how we currently treat MDD and would redirect the focus of treatment strategies.

However, more recently this approach has been questioned, undermining the efficacy of antidepressant medications and encouraging researchers to explore alternative treatments. In 1998, researchers began conducting the first clinical study of the psychedelic substance psilocybin with human participants (Hasler et al., 2004), opening the door to a new form of treatment.

Where Psilocybin Comes In: Mechanism of Action & Neuroplasticity

This is where psilocybin comes in. Psilocybin is a naturally occurring psychedelic substance found in over 200 mushroom species and was first synthesised by Albert Hofmann in 1958. It is a pro-drug, meaning it must be converted inside the body, and once in the body it is converted to psilocin (its biologically active form) via dephosphorylation.

The key to psilocybin’s success is its ability to offset the neurological mechanisms underlying depression. For example, Kraehenmann et al. (2015) found that psilocybin notably decreased amygdala reactivity, and that this correlated with an improvement in mood. The mechanism by which psilocybin brings about these effects is due to it being a pleiotropic drug – i.e. one which produces multiple different effects – and is multifaceted.

The compound is a serotonin receptor agonist, meaning it activates a biological response after binding to a receptor. In the context of psychedelic compounds, the key receptor is the 5-HT2A serotonin receptor. The subsequent stimulation of the 5-HT2A receptor by psilocybin (via its metabolite psilocin) is what leads to the psychedelic’s anxiolytic (i.e. anxiety-reducing) and antidepressant effects. One of the most significant of these effects is psilocybin’s ability to promote neuroplasticity. Neuroplasticity is essentially the brain’s ability to grow and form new pathways and connections, also known as ‘rewiring’. Neuroplasticity also supports the process of neurogenesis (the growth of new neurons) and therefore psilocybin could have a role in replacing the neurons lost in the cortex which underlie the loss of top-down regulation (Krystal et al., 2020).

Another pathway in which psilocybin takes effect is by lowering the functional connectivity throughout the Default Mode Network (DMN). In MDD, DMN hyperconnectivity has been identified as a significant factor – it is associated with excessive mind-wandering and rumination (Yan et al., 2019). Psilocybin’s effect upon the DMN appears to reduce this rumination and ‘free up’ cognitive resources which may contribute to the alleviation of the illness, allowing the individual to begin engaging in normal cognitive processes rather than a continued cycle of negative thought patterns (Carhart-Harris et al., 2017).

Clinical Longevity & Future Therapeutic Horizons

In addition to psilocybin being successful in achieving depression remission, we find that in most studies, effects tend to be maintained long term. For example, a study by Gukasyan et al. (2022) found that the antidepressant effects of psilocybin could still be observed up to 12 months following a single treatment session. Furthermore, 75% of the participants maintained a clinically significant response to treatment. In comparison, Barchas & Altemus (1999) found that discontinuation of traditional antidepressants showed relapse in the range of 50% within a year.

So, what could be in the future when it comes to psilocybin? Well, short term goals would be to conduct more research with larger cohorts and more diverse populations. While the results we have so far are extremely promising, there is still a call for research on a broader scale. That being said, research is growing rapidly, with 18 ongoing clinical trials of psilocybin-assisted therapy for treatment-resistant MDD registered at clinicaltrials.gov as of 2025.

Educational Glossary of Technical Terms

Psilocybin (4-HO-DMT): A naturally occurring tryptamine alkaloid prodrug found in fungi of the genus Psilocybe, converted in vivo to the pharmacologically active metabolite psilocin via hepatic dephosphorylation.

Major Depressive Disorder (MDD): A debilitating clinical mood disorder characterised by persistent low mood, anhedonia, cognitive impairment, and neurovegetative symptoms lasting at least two weeks, meeting DSM-5 diagnostic criteria.

Medial Prefrontal Cortex (mPFC): A key anterior hub of the Default Mode Network involved in self-referential thinking, emotional regulation, and rumination – hyperactive in depressive states.

Amygdala: An almond-shaped structure within the temporal lobe essential for fear conditioning, emotional memory consolidation, and threat detection – hyperreactive in MDD.

Default Mode Network (DMN): An interconnected set of brain regions active during passive rest, mind-wandering, and self-referential thought. Hyperconnectivity within the DMN is correlated with depressive rumination.

Orbitofrontal Cortex (OFC): A prefrontal brain region mediating reward appraisal, cost-benefit computation, and hedonic evaluation – dysregulated in anhedonic depression.

Anhedonia: The clinical inability to experience pleasure, joy, or reward from previously rewarding activities – a core diagnostic feature of Major Depressive Disorder.

Top-Down Regulation: The hierarchical neural control exerted by higher-order prefrontal cortical structures over subcortical limbic reactivity – impaired in depression, leading to emotional dysregulation.

Monoamine Deficiency Hypothesis (MDH): The classical pharmacological premise that depression is primarily caused by deficient activity of monoamine neurotransmitters (serotonin, noradrenaline, dopamine) – increasingly questioned by contemporary meta-analyses.

5-HT2A Receptor Agonist: A molecule that binds to and activates the serotonin 5-HT2A receptor subtype, triggering downstream signalling cascades responsible for psychedelic-mediated neuroplasticity and antidepressant effects.

Neuroplasticity: The fundamental structural and functional capacity of neural circuits to remodel, form new synaptic connections, and strengthen existing pathways in response to experience, learning, or pharmacological intervention.

Neurogenesis: The biological process by which new functional neurons are generated from neural stem and progenitor cells, primarily in the hippocampal dentate gyrus in adult humans.

Anxiolytic: A pharmacological agent or physiological mechanism that reduces clinical anxiety, nervous tension, and fear-related arousal.

Pleiotropic: The capacity of a single therapeutic compound to produce multiple diverse biological and clinical effects through distinct but interrelated pharmacological pathways.

About the Author

Isobel Jarvis

Author & Scientific Contributor · OpenMind Initiative

[Space reserved for Isobel Jarvis’s academic background, research interests, credentials, and biographical description. Please contact the OpenMind team to submit your author bio.]

Academic Bibliography & References

Barchas, J. D. & Altemus, M., 1999. Monoamine Hypotheses of Mood Disorders. Basic Neurochemistry: Molecular, Cellular and Medical Aspects, 6th ed.

Carhart-Harris, R. L. et al., 2017. Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Scientific Reports, 7, 13187.

Greenberg, P. E. et al., 2021. The Economic Burden of Adults with Major Depressive Disorder in the United States (2010 and 2018). PharmacoEconomics, 39, pp. 653–665.

Gukasyan, N. et al., 2022. Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up. Journal of Psychopharmacology, 36(2), pp. 151–158.

Hasler, F. et al., 2004. Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study. Psychopharmacology, 172, pp. 145–156.

Kraehenmann, R. et al., 2015. Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with Enhanced Positive Mood in Healthy Volunteers. Biological Psychiatry, 78(8), pp. 572–581.

Krystal, J. H. et al., 2020. Ketamine and the Neurobiology of Depression: Toward Next-Generation Rapid-Acting Antidepressant Treatments. Proceedings of the National Academy of Sciences.

Moncrieff, J. et al., 2022. The serotonin theory of depression: a systematic umbrella review of the evidence. Molecular Psychiatry, 28, pp. 3243–3256.

Pellegrini, L. et al., 2021. Relationship between anhedonia and the orbitofrontal cortex in major depressive disorder. Journal of Affective Disorders, 293, pp. 214–220.

Rolls, E. T., 2019. The orbitofrontal cortex and emotion in health and disease, including depression. Neuropsychologia, 128, pp. 14–43.

Rolls, E. T. et al., 2020. The orbitofrontal cortex, lateral prefrontal cortex, and their connections to the human amygdala in depression. NeuroImage, 214, 116775.

World Health Organization, 2025. Depressive disorder (depression). WHO Fact Sheet.

Yan, C. G. et al., 2019. Reduced default mode network functional connectivity in patients with recurrent major depressive disorder. Proceedings of the National Academy of Sciences, 116(18), pp. 9078–9083.