How Do Psychedelics Work? A Guide to Their Effects on the Brain and Mind in Australia

Psychedelics have captured global attention for their potential to treat mental health conditions. Since July 1, 2023, Australia has permitted the use of MDMA and psilocybin for specific conditions, making it the first country to legalise psychedelic-assisted therapy within a national healthcare framework . Nevertheless, many Australians remain curious about how these substances actually produce their effects. Consequently, understanding the neuroscience and therapeutic mechanisms is essential for anyone exploring this topic.

The Science of How Psychedelics Work

To understand how psychedelics work, we first need to understand the brain’s fundamental architecture. The human brain is composed of billions of neurons that form complex networks. These networks communicate through chemical messengers called neurotransmitters. Psychedelics primarily target one specific neurotransmitter system.

The Serotonin 2A Receptor: The Primary Target

Classic psychedelics like psilocybin, LSD, and DMT work primarily by activating the serotonin 2A receptor (5-HT2A) in the brain . These receptors are highly expressed on the layer 5 glutamatergic pyramidal neurons of the cortex . When a psychedelic binds to these receptors, it triggers a cascade of effects. Psilocybin, in particular, acts as a 5-HT2A receptor agonist, which means it stimulates these receptors and disrupts ongoing cortical activity .

MDMA works differently from classic psychedelics. MDMA is a serotonin releasing agent that also affects dopamine and noradrenaline . It blocks the reuptake of all three amines, enhancing their activity, especially serotonin. MDMA acts through 5-HT1A receptors to attenuate fear responding in the amygdala . This mechanism helps PTSD patients fully engage with their psychological treatments.

What Happens in the Brain?

Brain imaging studies have opened a window into the mechanisms of psychedelic-assisted psychotherapy. Several key changes occur during a psychedelic experience:

1. Disruption of the Default Mode Network (DMN)

The default mode network is a “resting-state” neural network correlated with self-referential thoughts and musings. It is associated with concepts such as the ego . Psychedelics reduce the activity of this network, which is associated with rumination about the past and self-referential thoughts. Disruption of the DMN helps patients “break out” of repetitive and rigid styles of thinking, feeling, and behaving.

2. Increased Brain Connectivity

Psychedelics temporarily alter activity and increase connectivity between novel neural networks within the brain . The serotonin 2A receptors in the brain trigger neuroplastic changes, both functional and structural, which appear to facilitate improvements in mental health conditions . Research has linked this increased connectivity to enhancing openness and promoting a form of “active coping” in the brain.

3. Collapse of Rigid Neural Patterns

Psychedelics cause a large-scale collapse of hard-wired neurological patterns . The collapse of patterned network connections leads to increased entropy in the brain and a dissolution of previously hard-wired and rigid connectivity . This allows for new connections to form between neural networks that do not usually interact.

4. Ego Dissolution

Psychedelics frequently produce profound personal or existential insights, feelings of empathy and self-compassion, and a sense of connection or unity with other people, things, and the world in general . These subjective experiences are correlated with therapeutic outcomes. Ego dissolution refers to the breakdown of the thought-filled, controlling and rigid aspects of our minds.

What Do Psychedelics Feel Like?

The subjective experience of psychedelics can vary widely depending on the substance, dose, setting, and individual mindset. In a therapeutic setting, psychedelics frequently produce a range of experiences.

Altered perceptions are common, including sensory hyperacuity, visual distortions, and changes in the sense of time . Emotional shifts such as feelings of empathy, self-compassion, and connection with others are also typical . Existential insights can include new understandings of oneself and one’s place in the world . Some patients experience access to unconscious material, bringing emotions, thoughts, beliefs, and traumatic memories to consciousness that may otherwise remain subconscious or hard to access .

These experiences can be intense and challenging initially. However, as with any good therapy, it is through the challenging aspects of the psyche, including fear and pain, that true healing can be found .

What Is Psychedelic-Assisted Psychotherapy?

Psychedelic-assisted psychotherapy involves more than simply taking the drugs. The settings in which psychedelics have been trialled all involve a series of psychotherapy sessions before the substance is used and after . This is to help the patient prepare for the effects of the drug, to begin working on the issues being treated, and to build a rapport with the therapist(s).

The process of psychedelic-assisted psychotherapy is based upon the ‘set and setting’ concept. The mindset of the user and the setting in which the drug is used are important for determining what the psychedelic experience will be like . PAT treatment usually involves some time in preparation, up to three dosing sessions, and a series of psychotherapeutic integration sessions, which help the patient to make sense of their experience and to preserve, protect and extend what is valuable within it .

In Australia, PAT is being conducted within university and industry clinical trials and in private hospitals and clinics . Although costs vary, a course of privately undertaken PAT is expensive, ranging widely but up to $35,000, although some limited rebates may be available .

The Australian Context

Australia’s approach to psychedelics is pioneering but carefully regulated. The Therapeutic Goods Administration (TGA) has permitted the use of MDMA and psilocybin for specific mental health conditions .

What Is Legal: MDMA is legal for treating PTSD, and psilocybin is legal for treatment-resistant depression . Under the rescheduling, current prescribing rights are limited to psychiatrists who have become authorised prescribers under the TGA’s Authorised Prescriber Scheme . For these specific uses, MDMA and psilocybin are listed as Schedule 8 (Controlled Drugs) medicines. For all other uses, they remain in Schedule 9 (Prohibited Substances) .

The Authorised Prescriber Pathway: To prescribe MDMA or psilocybin, psychiatrists must hold specialist registration as a psychiatrist with the Australian Health Practitioner Regulation Agency (AHPRA), have completed a Fellowship with the Royal Australian and New Zealand College of Psychiatrists (RANZCP), obtain approval from a Human Research Ethics Committee (HREC), and seek and obtain authorisation from the TGA under the Authorised Prescriber Scheme .

Conclusion

Psychedelics are powerful substances that temporarily alter brain function through activation of serotonin receptors. They work by disrupting rigid neural patterns, increasing brain connectivity, and facilitating profound personal insights. The evidence for their therapeutic potential is compelling, particularly for treatment-resistant depression and PTSD. However, they are not for everyone, and they require careful preparation, skilled professional support, and a controlled clinical setting. For those who have exhausted other treatment options, Australia’s pioneering framework offers a legally regulated pathway to access these promising therapies. For the vast majority of Australians, however, psychedelics remain prohibited substances with severe penalties for possession and supply.