How do Magic Mushrooms Affect the Brain

Regarding hallucinogens like psilocybin—the key compound in what are commonly known as “magic mushrooms” (for instance, Psilocybe cubensis)—it might be time to reassess traditional views on how they function in the human brain.

Though psilocin (the active component that psilocybin converts into) and other traditional hallucinogens like lysergic acid diethylamide (LSD) interact with a wide range of neurotransmitter receptors, their hallucinogenic effects are most closely associated with the activation of 5-HT2A serotonin receptors. Notably, studies involving 5-HT2A knockout mice have shown that these hallucinogens lose their effectiveness without this receptor. Furthermore, the hallucinogenic effects of psilocybin are negated in humans when 5-HT2A antagonists are administered beforehand. These pieces of evidence collectively reinforce the theory that psilocybin and similar hallucinogens produce their psychedelic effects primarily through the stimulation of 5-HT2A serotonin receptors.

Psilocybin, initially inactive, transforms into the active compound psilocin once metabolized. Psilocin engages multiple neurotransmitter receptors to regulate the activities of both excitatory pyramidal neurons and inhibitory GABA-ergic neurons. Psilocin’s binding affinities, noted as negative logarithmic values in nanomoles (pKi) from the National Institute of Mental Health’s Ki Database, reveal its broad receptor interactions. It impacts large excitatory pyramidal neurons and smaller inhibitory neurons, possibly enhancing or inhibiting neurotransmission. Ultimately, Psilocin typically reduces overall brain activity and connectivity, as evidenced by fMRI measurements.

The exact neuronal mechanisms through which classic hallucinogens like Psilocybin exert their psychedelic effects are still debated, although some research suggests that substances like LSD can activate 5-HT2A serotonin receptor signaling, boosting activity in pyramidal neurons. This glutamatergic activation aligns with findings that 5-HT2A receptors are predominantly found on Layer V glutamatergic neurons, although they’re also present on GABA-ergic interneurons, where 5-HT2A agonists may enhance inhibitory neuronal activity. Thus, the effects of hallucinogens might stem from their influence over both excitatory and inhibitory neural circuits, potentially enhancing either type of neuronal activity to produce psychedelic effects. However, comprehensive human studies on these substances have been scarce since the early 1960s due to various medical, legal, and societal challenges.

In a significant study published in PNAS, Carhart-Harris and colleagues begin to address these gaps. They show that Psilocybin lowers indicators of neuronal activity—namely cerebral blood flow and blood oxygen level-dependent (BOLD) signals—in crucial brain areas associated with the effects of psychedelic drugs. They also observe a reduction in brain “connectivity,” as measured by pharmaco-physiological interaction.

For their research, Carhart-Harris et al. enlisted 15 experienced hallucinogen users who underwent scans before and after intravenous doses of either a placebo or 2 mg of Psilocybin. The participants’ subjective experiences were assessed, with Psilocybin inducing significant psychedelic effects, including altered states of consciousness, changes in time perception, and visual alterations.

These subjective changes coincided with decreased cerebral blood flow in key regions known to be involved in psychedelic drug effects, such as the anterior and posterior cingulate cortices and the thalamus. Notably, the intensity of the psychedelic experience was closely linked to reductions in blood flow in the thalamus and anterior cingulate cortex. Carhart-Harris and his team also noted what they termed a decrease in “functional connectivity” between significant brain areas, suggesting an overarching diminution in brain activity coordination during Psilocybin exposure.

Unveiling the Neural Choreography: How Psilocybin Disrupts and Reconfigures Brain Connectivity


Psilocybin seems to reduce brain “connectivity” as measured through pharmaco-physiological interactions, particularly affecting the prefrontal cortex and other key areas, suggesting an overall reduced connectivity.

These findings align with the theory that psilocybin decreases activity in crucial brain regions and networks involved in hallucinogenic effects. This is a significant shift because it challenges the traditional view that hallucinogens primarily boost excitatory neurotransmission and overall brain activity.

The work of Carhart-Harris and his team is also crucial as it demonstrates convincingly that, with proper safeguards, the effects of psychedelic drugs can be methodically analyzed in human subjects. Psychedelic drugs uniquely alter human consciousness and perception, and these studies provide valuable insights into the brain structures that underpin human consciousness.

How Do Magic Mushrooms Affect the Brain?

The study utilizes brain scans from nine subjects who were administered either psilocybin or a placebo. These scans helped create a “whole-brain connectome,” a comprehensive map of the brain’s neurons and the neurotransmitter activity occurring within.

Ordinarily, the human brain operates like a well-oiled machine, with neurons firing and neurotransmitters traveling established routes much like vehicles on a highway. Under the influence of magic mushrooms, however, these networks become “destabilized,” as Kringlebach puts it.

Research indicates that alongside this destabilization, new networks begin to form. It’s akin to cars leaving the highway to explore new routes on backroads.

The study delves into how psilocybin and other psychedelics, which mimic serotonin—a neurotransmitter associated with happiness—impact the brain more extensively than just altering serotonin levels.

Kringlebach is particularly interested in how neurotransmission dynamically alters activity across the entire brain network, influencing neurotransmitter release in turn.

The findings suggest that the brain leverages these changes by synchronizing neuron activity with neurotransmitter release, creating a balance crucial for its function. When these processes are uncoupled in their models, the typical network destabilization seen with psilocybin use does not occur. Similarly, altering the serotonin receptors (specifically the 5-HT2A receptors targeted by psilocybin) to different types disrupts this pattern.

This highlights the necessity for both specific receptors and particular patterns of neuron activity for psilocybin to effectively influence brain function.

The Future of Magic Mushrooms: Unraveling Brain Mysteries and Therapeutic Potential

Understanding Psilocybin’s Mechanisms for Therapeutic Use

Knowing that both receptors and neuron activity are crucial, Kringlebach believes these insights could revolutionize how we use psilocybin as therapy. These models offer a new perspective on an enduring brain mystery. “It has always puzzled scientists how the brain’s fixed anatomical structure can host such a variety of brain states—from alertness to deep sleep and intense psychedelic experiences,” Kringlebach explains.

Despite having a limited amount of neurological ‘hardware,’ the brain runs complex ‘software’ that enables dreams, consciousness, and profound drug-induced experiences. Magic mushrooms exemplify the brain’s ability to adapt its fixed resources for vastly different functions, contingent on the specific components involved. The challenge lies in discovering what tools the brain requires to run diverse mental ‘programs.’

New Models for Brain Function: Hope for Neuropsychiatric Disorders

Looking ahead, Kringlebach and his team are optimistic that their model could lead to novel ways of using our brains to treat conditions like depression. “This new model will furnish us with the essential, causal tools for potentially crafting new interventions to alleviate human suffering in neuropsychiatric disorders,” he states.

The Therapeutic Promise of Psychedelics: Insights from Recent Studies

Recent therapeutic trials using classic psychedelic substances like psilocybin (from magic mushrooms) or LSD highlight significant wellness benefits, including improvements in depression and anxiety. These positive effects are often attributed to a phenomenon known as “ego dissolution,” where individuals lose the sense of a distinct self, merging with the world around them. However, the biochemical underpinnings of this effect have remained elusive until now.

Research Breakthroughs in Understanding Psychedelic Effects

Natasha Mason from Maastricht University in the Netherlands, alongside her colleagues, embarked on a study with 60 participants who were experienced with psychedelic drugs, though abstinent for three months prior to the study. Half received a placebo while the other half took a moderate dose of psilocybin.

The team employed proton magnetic resonance spectroscopy (MRS) to measure levels of glutamate and other neurochemicals in the medial prefrontal cortex (mPFC) and hippocampus—areas critical to the psychedelic experience. They also examined how these drugs affect “functional connectivity” across brain regions.

Linking Glutamate Levels to Psychedelic Experiences

Six hours post-administration, the subjects reported their experiences, confirming increases in ego dissolution and altered consciousness. Notably, the study revealed for the first time in humans that psilocybin elevates glutamate levels in the mPFC while reducing them in the hippocampus. These fluctuations in glutamate were directly associated with different dimensions of ego dissolution: increases in the mPFC correlated with negative effects like loss of thought control and anxiety, whereas decreases in the hippocampus were tied to positive experiences of unity and spiritual-like states.

These findings deepen our understanding of how psychedelics manipulate brain chemistry and suggest new pathways for exploring their therapeutic potential.

Exploring Memory and Self: The Role of the Hippocampus in Psychedelic Experiences

The Hippocampus and the Sense of Self

The hippocampus, a crucial structure for memory, may play a significant role in how psychedelic drugs influence our sense of self. Previous research suggested that psychedelics might temporarily impede access to personal memories, contributing to a diminished sense of individuality. The latest findings propose that alterations in hippocampal glutamate levels are central to this phenomenon.

The Complex Relationship Between Glutamate, Ego Dissolution, and Anxiety

While increases in glutamate in the medial prefrontal cortex (mPFC) are associated with the less pleasant aspects of ego dissolution and anxiety, the overall impact of psychedelics on anxiety disorders remains somewhat paradoxical. Although psychedelics primarily affect the 5-HT2A type of serotonin receptor, leading to immediate shifts in the glutamate system and potentially short-term anxiety, the long-term decrease in anxiety may hinge more directly on 5-HT2A receptor activation itself rather than changes in glutamate levels.

Glutamate and Brain Plasticity: Potential Insights into Depression Treatment

It’s also hypothesized that stimulating glutamate networks via the 5-HT2A receptor enhances levels of Brain-Derived Neurotrophic Factor (BDNF), which is essential for the health and growth of new brain cells. Studies in animals have shown that psychedelics can foster brain plasticity. Given that reduced plasticity is a feature of major depression and stress disorders, the recent evidence suggesting that psychedelics could boost neuroplasticity in the human cortex by increasing glutamate levels is promising. This might illuminate how these drugs counteract depression.

The Need for Further Research and Its Implications

Although more research is necessary to unpack these complex biochemical processes fully, the burgeoning interest in the therapeutic potential of psychedelics is undeniable. The new study adds valuable detail to our understanding of the neurobiology underlying the psychedelic state, offering a neurochemical explanation for how these substances alter the sense of self and could produce therapeutic effects, as observed in ongoing clinical trials. This body of work is crucial as it continues to uncover how psychedelics may facilitate profound therapeutic transformations.

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