What is Psilocybin and How Could it Help Depression?
Updated: Sep 22
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 on 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 Postpartum Depression to Seasonal Affective Disorder to Bipolar Disorder. It is an illness that not only affects a person’s mental state, but that of those around them. It can render people unable to hold down a job, maintain relationships or live a normal and happy life. 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 cognition of those affected presents as rigidly pessimistic. Researchers have identified the brain areas where activity is most altered by depression, providing insight into where symptoms come from. The excessive negative feeling – dysphoria – has been attributed to hyperactivity in a part of the brain involved in emotion, motivation and sociability, known as the medial prefrontal cortex (Krystal, 2021). It has a large role in self-reflection, which explains why, when overactive, people can become exceedingly self-critical, which leads to self-loathing.
The disorder commonly entails increased dwelling on the negative and a perceived inability to see the good in situations. These thought processes have a physical explanation, stemming from the amygdala. The amygdala is a part of the brain that is involved in the processing of emotion, specifically negative or fearful emotions. It’s involved in a network in the brain (Ventral Limbic Network inside the Default Mode Network) which increases in connectivity during depression. Over time, the amygdala / its nuclei can ‘swell’ (increase in size), leading to neuron (brain cell) damage and changes in processing and output (Sarah Wilson, 2022). Logically, this explains the focus on the negative as increased firing in this location means excessive processing of unpleasant and fearful memories.
So, 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.
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, hypofunction in the brain areas involved in attention, emotional drive, memory, and movement leads to these functions being dampened. These areas are in the frontal-striatal network, and within this network is the part of the brain that controls reward processing and impulsivity, known as the Orbitofrontal Cortex (Rolls, et al., 2020). Its lowered activity can explain why those with depression find it hard to feel pleasure and enjoyment (anhedonia) and some make hasty decisions driven by a lack of inhibition.
The outcome of these alterations in activity level is that the reactive, ‘lower down’ regions in the brain gain control over the logical, ‘higher up’ regions. Top-down regulation is the process of the cortex regulating emotional reactions and responses. It can be likened to a dam with holes being knocked into it – normally it controls the influx and stops the brain from being flooded, but in MDD this control weakens, and the unregulated negative emotions can take over. This change in dominance explains the loss of control over negative thoughts and emotions in patients (Li, et al., 2018). Overall, depression causes alterations in the brain that lead to changes in its ability to function, which causes the mood disorder. The physiological changes - swelling and shrinkage – can also worsen over time, leading to a more severe presentation, which makes remission harder to achieve.
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 based on the Monoamine Deficiency Hypothesis (MDH), a proposed explanation for depression. The MDH focuses on a decrease in levels of 3 key neurotransmitters used to spread information throughout our brains: serotonin (often the focus and the target of SSRIs), norepinephrine and/or dopamine. This idea stems from various studies, one of which involves a drug (Reserpine) being used to deplete the monoamine stores, which induced depression and supported the notion that a deficiency will trigger disorder onset. Similarly, when administered a monoamine oxidase inhibitor (Iproniazid), which prevents the breakdown and removal of the monoamines, patients experienced an ‘antidepressant’ effect (Delgado, 2000; Barchas & Altemus , 1999). Therefore, this research worked in favour of the MDH, establishing the monoamines’ roles in depression control.
However, more recently this approach has been questioned, undermining the efficacy of antidepressants and therefore calling for research to be conducted into alternatives. Recent reviews have debunked the consensus that depression is caused by underactivity of serotonin, meaning we must look for causes elsewhere (Moncrieff, et al., 2022). One third of patients experience no improvement in symptoms when on antidepressants, and treatment-resistant depression is extremely common (Güneş, et al., 2023). We also find many users of these medications report a range of unpleasant side effects. Additionally, patients will only experience the benefits of antidepressants while actively taking them, which turns the medication into a lifelong commitment, tying users to purchasing and taking them forever. Since the identification of these flaws, research has turned to rethinking the way in which we treat depression, sparking interest in new compounds.
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. The key to psilocybin’s success is its ability to offset the neurological mechanisms underlying depression. Many overactive pathways in depression can be reduced by psilocybin, and those that are underactive can be increased. Generally, psilocybin works by increasing neuroplasticity while downregulating the default-mode network (known to be upregulated in depression) and reducing the activity in the amygdala. Several of these same mechanisms also reduce anxiety symptoms (it’s ‘anxiolytic’), meaning in addition to improving mood, it can reduce panic, nervousness, fear, and muscle tension, which often coincide with depression - giving psilocybin its ability to produce multiple biological effects (pleiotropic ability).
The compound is a serotonin receptor agonist, meaning it activates a biological response after binding to the serotonin receptor, which sets off a chain reaction in the brain that alters perception, mood, cognition, emotional regulation, and attention. Psilocybin produces a wide spectrum of physiological and psychological effects; this includes an ability to improve neuroplasticity– aiding the repair of neurons – and possibly even playing a role in neurogenesis – neuron generation (Wang, et al., 2023). In depression, neuroplasticity is reduced, which has been linked to the worsening of symptoms alongside increased fear and negative emotion processing. The activation of the 5-HT2A receptor additionally reduces the amygdala’s response to visual stimuli, as it reduces the connectivity between the amygdala / limbic system and the prefrontal cortex/neocortex. Therefore, this works to reduce fearful emotions and, over time, reduce the ‘swelling’ of the brain region.
Another pathway in which psilocybin takes effect is by lowering the functional connectivity throughout the default-mode network (DMN). The DMN is a collection of brain regions, including the medial prefrontal cortex, which were previously mentioned as they exhibit pathogenic overactivity with the onset of depression. Psilocybin can interfere with this to provide a level of control over our consciousness, self-reflection and rumination (Rainer Kraehenmann, 2016). Overall, reducing the DMN helps reduce all the negative ‘noise’ someone with depression experiences and helps someone regain control over their thoughts and feelings.
In addition to psilocybin being successful in achieving depression remission, we find that in most studies, people experience little to no adverse effects. It can also be taken sparingly; one dose can have positive effects on people for months on end. This would mean it could be administered on a periodic schedule as opposed to every single day. This makes psilocybin a much more attractive treatment due to it fitting better into people’s lives; it also makes it easier to regulate.
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.
There is some evidence to suggest that psilocybin could be used to treat OCD (specifically compulsions) (Luca Pellegrini, 2025), alcohol use disorders (Mathias Ebbesen Jensen, 2022), addiction (Pim B van der Meer, 2023) and as previously mentioned, it could possibly play a role in reduction of anxiety or panic. This displays the wide possibilities related to this substance.
So, 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
A Biomedical Science student at the University of Sheffield, currently pursuing a placement year with the Sheffield Institute of Translational Neuroscience.
Academic Bibliography & References
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Delgado, P. L., 2000. Depression: the case for a monoamine deficiency. The Journal of clinical psychiatry , 61(6), pp. 7-11.
Güneş, B., Koenhemsi, L. & Erbaş, O., 2023. New Approach for Treatment-Resistant Depression. Biochemistry, Issue 2632-0983.
Krystal, J., 2021. How Depression Affects the Brain. [Online]Available at: How Depression Affects the Brain > News > Yale Medicine
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Sarah Wilson, M. B., 2022. How Depression Affects the Brain and How to Get Help. [Online] Available at: https://www.healthline.com/health/depression-physical-effects-on-the-brain[Accessed 1 November 2023].
Wang, S.-M.et al., 2023. Current Understanding on Psilocybin for Major Depressive Disorder: A Review Focusing on Clinical Trials. Clinical Psychopharmcaology and Neuroscience, 22(2), pp. 222-231.
WHO, 2025. World Health Organisation. [Online] Available at: https://www.who.int/news-room/fact-sheets/detail/depression[Accessed 29 August 2025].
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