The Default Mode Network and Psychedelics

Somewhere around page forty of a 2012 Robin Carhart-Harris paper, I remember putting my coffee down and just sitting with it for a moment. The default mode network , a set of brain regions most neuroscience students learned as the "resting state" network , wasn't resting at all. It was doing something. And psilocybin, the compound in certain fungi, appeared to suppress it in ways that looked unlike anything produced by conventional pharmacology. I'd been reading brain imaging literature for years by that point, and this felt genuinely strange.

Before we go any further: psilocybin is a Schedule 9 prohibited substance under Australia's Poisons Standard. Possessing, using, or supplying it outside a specific, narrow regulatory pathway is a criminal offence in every Australian state and territory. Since 1 July 2023, the TGA has allowed Authorised Prescribers to prescribe psilocybin (rescheduled to Schedule 8 for that purpose) to specific patients under tightly defined conditions , but that pathway involves a specialist psychiatrist, TGA approval, and formal oversight. It is not broadly accessible, and it is not something to self-administer based on anything you read here or anywhere else online. That framing is the only responsible way to start this piece.

With that established, let's look at the actual neuroscience; because it's worth understanding on its own terms.

What the default mode network actually is

The default mode network (DMN) is a loosely coupled set of brain regions that show correlated activity when a person is not engaged in a demanding external task. The medial prefrontal cortex, posterior cingulate cortex, precuneus, and angular gyri are the most consistently identified nodes. Early fMRI researchers noticed these regions lit up during "rest" conditions and initially treated them as background noise. It took roughly a decade of research before the field began to appreciate that the DMN appears to underpin self-referential thought: mind-wandering, autobiographical memory retrieval, thinking about other people's mental states, and the general sense of a continuous, narrative "self."

Disruption to the DMN, through injury, disease, or pharmacology, tends to produce altered experiences of self-continuity. That's not a therapeutic claim. It's an observation about mechanism that predates psychedelic research by years.

Psilocybin's pharmacological mechanism

Psilocybin is a prodrug. After ingestion it's rapidly dephosphorylated to psilocin, the active compound. Psilocin is a partial agonist at the serotonin 5-HT2A receptor, with additional activity at 5-HT2C and 5-HT1A subtypes. The 5-HT2A receptor is expressed at high density in pyramidal neurons in layer V of the prefrontal cortex; exactly the cortical layers most involved in integrating top-down predictive signals. You can read more about how receptor pharmacology shapes drug classification on our Schedule 8 (Controlled Drug) glossary page.

The key point is that psilocin's agonism at 5-HT2A doesn't simply "add" serotonin signalling. It appears to disrupt the tightly regulated balance of excitation and inhibition that maintains stable large-scale network dynamics. The DMN, which depends on that balance for its characteristic coherence, becomes less coherent. Simultaneously, regions that don't normally communicate strongly with each other show increased cross-network connectivity.

The brain imaging evidence, and its limits

The foundational imaging work came from Imperial College London. A 2012 study by Carhart-Harris and colleagues, published in PNAS, used arterial spin labelling and BOLD fMRI to measure cerebral blood flow and connectivity in healthy volunteers after intravenous psilocybin. Reported doses in that study were low by community accounts, 2mg intravenously, a route and dose chosen for safety monitoring in a controlled clinical setting. The results showed decreased blood flow and BOLD signal specifically in DMN hubs, with the degree of decrease correlating with subjective ratings of "ego dissolution." Those are reported findings from a published, peer-reviewed study with specific methodological constraints. They are not a protocol for anything.

A 2021 paper in Nature Medicine (Carhart-Harris et al.) and subsequent work from centres in the US and Europe have broadly replicated the finding of acute DMN suppression and increased cross-network connectivity. But the literature has real limitations that I think sometimes get smoothed over in popular accounts. Sample sizes are generally small; many studies have fewer than thirty participants. Most early studies used healthy volunteers, not clinical populations, so extrapolating to any particular condition is scientifically premature. The intravenous route used in some early studies doesn't translate directly to oral administration. And the relationship between acute network changes and any lasting effect on subjective experience is not well characterised.

Honestly, the field is at an early but genuinely interesting stage. Calling any of this "proven" mechanism would be overstating it.

The entropic brain hypothesis

One theoretical framework that's gained traction is Carhart-Harris's "entropic brain" hypothesis, first formally published in 2014. The idea, loosely, is that psychedelics increase the entropy of brain activity, moving the system from a more ordered, constrained state toward a higher-dimensional, less predictable one. The DMN suppression fits this model: if the DMN is partly responsible for maintaining a stable, low-entropy "default" self-narrative, its disruption would correspond to the dissolution of that narrative and the flooding of consciousness with less filtered perceptual content.

It's a theoretically elegant framework. I'd argue it's still more hypothesis than established fact, the entropy metrics used in the literature depend on methodological choices that aren't universally accepted, and replication across imaging modalities has been uneven. But it has shaped a lot of the subsequent research agenda, and it's the reason the DMN became the focal point for psychedelic neuroscience specifically.

Comparing DMN effects across compounds

Psilocybin isn't the only compound studied in this context. LSD (lysergic acid diethylamide), DMT (N,N-dimethyltryptamine), and mescaline are all Schedule 9 prohibited substances in Australia; possession or supply outside the authorised prescriber pathway (which currently applies only to psilocybin and MDMA) remains a criminal offence. Ketamine occupies a different regulatory category as a Schedule 8 anaesthetic with some off-label use under medical supervision.

Across the serotonergic psychedelics, the general pattern of DMN suppression and increased cross-network coupling appears consistent in published imaging studies, though the precise network topographies differ. Cannabis-derived compounds, including tetrahydrocannabinol (THC), also alter DMN connectivity, but through a completely different receptor system, the endocannabinoid system, acting primarily at CB1 receptors concentrated in cortical and subcortical regions. The phenomenological similarities between cannabis and psychedelic states are often noted anecdotally, but the underlying network pharmacology is mechanistically distinct.

Where Australian regulation currently sits

The TGA's July 2023 rescheduling of psilocybin to Schedule 8 for use by Authorised Prescribers was a significant regulatory step, the first of its kind globally at a national level. But the details matter. Prescribing is restricted to consultant psychiatrists who have obtained Authorised Prescriber status from the TGA. Sessions must be conducted in controlled clinical settings with trained supervision. The Special Access Scheme pathway remains an option for individual patients outside that framework, again under strict conditions.

None of this opens a path for general access. The Australian Drug Foundation's resources on the legal status of psychedelics remain clear: outside these narrow clinical frameworks, psilocybin possession and use is illegal, and the criminal penalties vary by jurisdiction but are substantial. If you're a clinician interested in the Authorised Prescriber pathway, the TGA's website is the correct starting point; not this article.

The research landscape is moving, though. Several Australian universities have active psilocybin research programmes operating under the relevant TGA exemptions for clinical trials. That work will, over time, produce better-powered studies with more rigorous methodology. The imaging science of the DMN is genuinely worth watching, not because it promises any particular outcome, but because the basic neuroscience of self-referential cognition is fascinating on its own terms.

I was practising a Bill Evans voicing at the piano last week, badly, as usual; and found myself thinking about the DMN. Evans described his playing as finding "the space between the notes." Whether that's connected to anything in the neuroscience of default-mode suppression, I genuinely don't know. But it's the kind of question that keeps me reading the literature anyway.

Sources

• TGA permits prescribing of psychedelics for certain mental health conditions, Therapeutic Goods Administration (TGA)
• Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin, NCBI / PNAS (Carhart-Harris et al., 2012)
• Magic mushrooms drug facts; Australian Drug Foundation (ADF)
• The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs, NCBI / Frontiers in Human Neuroscience (Carhart-Harris et al., 2014)

, Daniel Okoro, Psychedelic science & law writer

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