PT Neurons Hold the Secret to Psilocybin’s Mental Health Impact

Shrooms are not only about trippy visuals and euphoria vibes. These ‘magic mushrooms’ are also known for their amazing therapeutic promise. But have you ever wondered just what’s behind this hallucinogenic kick that you get from the shrooms? 

Well, the star of this show is psilocybin, which is not present in all mushrooms but only in certain types. This active ingredient is what brings the ‘magic’ in ‘magic mushrooms,’ and it is gaining a lot of limelight not only for its hallucinogenic effects but also for its potential to heal the mind.

A study conducted¹ by the Department of Psychiatry of Washington University School of Medicine last summer found that just a single dose of psilocybin is enough to produce rapid and persistent therapeutic effects in humans.

Studies have also found that psilocybin is effective in treating depression and anxiety, as well as tobacco and alcohol use disorders. The decline in clinical symptoms has actually been shown to last as much as twelve months after only one to three psilocybin administrations. 

A separate study² from a few years ago by the Center for Psychedelic and Consciousness Research, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, found that psilocybin may even increase emotional and brain plasticity. The findings also supported the hypothesis that negative effects may be a therapeutic target for psilocybin.

While psilocybin is known for eliciting euphoria, peacefulness, and spiritual awakening, its effects go far beyond these.

Other potential effects of this psychedelic compound involve distorted thinking, derealization, depersonalization, dizziness, drowsiness, paranoia, confusion, nausea, frightening hallucinations, and, more importantly, an altered perception of time and space and intense changes in mood and feeling.

Despite this, the use of magic mushrooms has been surging both recreationally and to improve mental health.

While psilocybin has seen broad adoption and promising great advances, it is still not well understood. So, researchers and scientists are constantly trying to understand this classic psychedelic compound as well as the changes it can bring to the human mind.

With the aim of aiding this, researchers from Cornell University went on to study the classic psychedelic. They revealed two main brain mechanisms that help clarify just how psilocybin is able to create long-lasting antidepressant effects.

They have identified specific neurons, frontal cortical PT neurons, and 5-HT2A, a serotonin receptor, as essential components mediating psilocybin’s long-term drug action, brain plasticity, and depression-related behavior.

The Key to Psilocybin’s Therapeutic Action

The psychedelic is known for effectively treating psychiatric disorders, with clinical trials showing that one or two sessions of psilocybin-assisted therapy reduce depression symptoms for many weeks. 

It has been hypothesized that antidepressants work by forming and strengthening synapses in the prefrontal cortex. This prevents synaptic dysfunction in depression. 

In line with this framework, studies in mice have shown that a single dose of psychedelic drugs such as psilocybin results in an increase in the size and density of apical dendritic spines, which play a crucial role in synaptic plasticity and information processing, in cortical pyramidal cells.

However, neurons are diverse, so it’s unclear how psychedelic-evoked neural adaptations show up in different excitatory cell types. 

In particular, there are two main, non-overlapping populations of cortical pyramidal cells, the most common neurons in the cerebral cortex. These include intratelencephalic (IT) neurons and pyramidal tract (PT) neurons, each with distinct cellular properties.

These neurons also participate in different long-range circuits because they send different axonal projections (pathways formed by the long, slender projections of neurons that transmit electrical impulses to other neurons) to communicate with different brain regions.

These pyramidal cell types support a range of behavioral functions, and their impairments have been linked to neuropsychiatric disorders.

As for how these neurons (PT and IT) respond to psilocybin, existing studies provide different signals regarding just how they should contribute to psychedelic drug action.

The latest study measured the acute and long-term impact of psilocybin on PT and IT neurons in mice’s medial frontal cortex. To investigate the impact of psilocybin on the pyramidal cell types, the researchers used cell-type-specific electrophysiology, chemogenetic perturbation, and in vivo optical imaging.

It has been found that PT neurons are specifically driven by psilocybin to increase synaptic calcium transients, which are brief increases in calcium ion concentration that are crucial for synaptic plasticity. These transients also boost spiking activity in animals. 

While psilocybin evokes structural plasticity in both PT and IT neurons, the study further found that causal manipulations show frontal cortical PT neurons are needed for psilocybin’s effects in stress-related behavioral assays. 

In addition, the study noted that the 5-HT2A receptor is needed for psilocybin-evoked structural remodeling in PT neurons. As a subtype of the serotonin receptor, the 5-HT2A receptor is involved in various physiological functions and conditions like psychosis and hallucinogenic effects. 

This identification has the potential to allow pharmaceuticals to deliver the mood-altering benefits of psilocybin while restraining the hallucinatory trip by targeting the specific neurons and their specific serotonin receptor in the medial frontal cortex.

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Psilocybin’s Neural Journey

The latest study, which was supported by the National Institutes of Health, the Connecticut Department of Mental Health and Addiction Services, Source Research Foundation, and One Mind–COMPASS Rising Star Award—was led by Alex Kwan, an associate professor of biomedical engineering. It built on a previous study.

The study from 2022 used optical microscopy along with other tools to uncover how psychedelics light up the brain’s neuropathways, which are the connections between neurons in the brain and nervous system.

A year before this, Kwan used two-photon microscopy to demonstrate that a single dose of psilocybin led to a 10% increase in the number of neuronal connections in a mouse brain. 

Kwan’s other study from a few months ago, late last year, meanwhile, shared insights into how psychedelic drugs, psilocybin and mescaline, reduce anxiety. The psychedelic DOI (2,5-dimethoxy-4-iodoamphetamine) does this by activating the ventral hippocampus  (vHPC), which is involved in social memory and emotion, and the fast-spiking interneurons there, which are known for silencing other neurons and make up 10% to 15% of cells in the vHPC region.

For his work, Kwan received the 2022 One Mind Rising Star Award for Mental Health Research, and then went on to find the answers behind the creation of new neuronal connections, which pathways are strengthened, and if these changes support psilocybin’s therapeutic effects.

So, using two-photon microscopy, viral tracing, and optogenetic manipulations, they mapped the brain’s neural response to psychoactive chemicals.

At the time, Kwan noted the “big void in terms of understanding” what psychedelics do to the brain at the neural circuit level. “There’s a chain of events that happen that ultimately lead to acute and longer-lasting behavioral changes that might be useful for treatment. But in between a lot of that is a black box,” he added.

In the latest study, the idea was to identify just where the neuronal connections grow in cell types. According to Kwan:

“We started playing around with these cell types, and we asked: Which are important for psilocybin’s behavioral effects? If we silence some of these neurons, will psilocybin still be able to do its thing and be therapeutic?” 

For therapeutic effects, it is the frontal cortex that is important. Meanwhile, the subjective perceptual effects, aka “the trip,” are likely to depend on another region of the brain, say, visual pathways. So, this could have important implications for pharmaceutical treatment.

As Kwan noted, the focus of the pharmaceutical companies is currently on developing drugs that can eliminate the trip while providing the benefits of treating mental illnesses. According to Kwan, who led this project:

“But what this work shows is that that could be difficult, because in the end, they target the same receptor. So one might think about just delivering the drug to some specific brain areas, which can be a better way to do it.” 

For the study, the researchers used two-photon microscopy (TPM), a fluorescence imaging technique that enables the visualization of living tissue in great depth, on genetically engineered mice and targeted PT neurons and IT neurons in their brains.

While silencing the IT neurons didn’t change the psilocybin’s behavioral effects, inactivating the PT neurons made the drug ineffective. This proved that PT neurons and their pathway, which goes from the frontal cortex down into the midbrain and brainstem, are crucial for psilocybin’s effects.

This cell type’s 5-HT2A receptor was found to be just as important. When the receptors were knocked out, the positive behavioral effects of psilocybin also disappeared. The receptor plays an essential role in experiencing acute, short-term hallucinatory trips. 

“This suggests that it’s really the same serotonin 2A receptor that is also quite important for the long-term behavioral effects. The brain circuitry is where it differs.”

– Kwan

Overall, by presenting the cell types and receptors that are responsible for psychedelic action, the study highlights the neural circuits that may be promising targets for neuromodulation and precision treatment.

Innovative Company

Mind Medicine (MindMed) Inc. (MNMD +16.16%)

Among companies actively exploring psilocybin and related therapeutic areas, the NASDAQ-listed Mind Medicine is a prominent one, which is developing psychedelic-inspired medicines, including psilocybin derivatives.

MindMed is a biopharmaceutical company developing new candidates to treat brain health disorders. It aims to lead treatments that unlock new opportunities to improve patient outcomes by building a pipeline of product candidates focused on neurotransmitter pathways.

With its products, the company will offer better outcomes by restoring neural pathways for sustained remission, improving patient experience through single administration, lowering costs through timely screening and early treatment, and improving clinician experience via treatments with meaningful improvements.

In particular, the company strives to deliver on the therapeutic potential of psychedelics and other novel compounds to address Generalized Anxiety Disorder (GAD), which affects 20 million adults, Major Depressive Disorder (MDD), affecting 31 million people, and Autism Spectrum Disorder (ASD), influencing 5.4 million adults in the U.S.

Now, the $368.55 million market cap company’s shares are currently trading at $4.80, down 29.74% this year so far. This disappointing stock performance comes after a strong 2024, though prices have been muted for more than two years now and far from the $154 high MNMD put in March 2017.

The latest rough patch for MNMD stocks comes as the entire US stock market faces turbulence amidst President Donald Trump’s tariff announcement, which has created a concern for a trade war. 

The broad stock market is currently experiencing a deep sell-off with the S&P 500 down 19%, the Nasdaq down 23%, and the Dow Jones down 16.4% from their respective all-time highs (ATH) hit earlier this year.

This week, ​​Trump also said the “major” tariff on pharmaceutical imports will be announced soon.

Then there’s the fact that as a clinical-stage biopharmaceutical company whose focus is on psychedelic-inspired medicines, MindMed operates in a highly speculative and volatile sector. In such industries, investor sentiment can be particularly sensitive to clinical trial outcomes, regulatory developments, and shifts in the broader economic environment. With that, MNMD’s EPS (TTM) is -1.81 and the P/E (TTM) ratio is -2.71.

This news comes just a few months after the company announced its addition to the Nasdaq Biotechnology Index (NBI) in December.

“We are in a pivotal phase in our growth and the addition to the NBI further validates our potential in delivering long-term value to shareholders as we progress our pipeline and aim to deliver transformational innovation for people living with brain health disorders.”

– CEO Rob Barrow

This achievement marked the end of a “transformational year” in which the company successfully executed many important milestones. These included receiving a patent for the MM120 orally disintegrating tablet (ODT), expanding the pipeline of MM120 ODT for MDD, and launching Voyage, the Phase 3 study of MM120 ODT in GAD. Its MM120 Phase 2b study in GAD also received a breakthrough therapy designation from the FDA.

MM120 Orally Disintegrating Tablet (ODT) is MindMed’s proprietary and pharmaceutically optimized form of LSD, which is being explored for its potential applications in many serious brain health disorders. MM402, meanwhile, is MindMed’s proprietary form of R(-)-MDMA, which is specifically for the treatment of core symptoms of ASD.

Most recently, the company appointed Matt Wiley as its Chief Commercial Officer. With extensive experience in introducing neuroscience therapeutics, Wiley will oversee the commercial strategy for the potential launch of its first product, MM120.

This follows MindMed successfully dosing the first subject in the Phase III Panorama study of a proprietary form of LSD, MM120 ODT, for GAD treatment. The 52-week trial aims to enroll about 250 subjects and will take place across the US and Europe. According to Chief Medical Officer Dan Karlin:

“MM120 ODT represents a potentially life-changing treatment for people living with GAD, and if our Phase III development programme is successful, it could offer a differentiated and compelling option for one of the most significant unmet needs in psychiatry.”

When it comes to company financials, it reported having cash and cash equivalents of $273.7 million at the end of 2024, compared to $99.7 million by the previous year-end. MindMed actually raised $250 million through two equity financings from several new institutional investors that will extend its cash runway into 2027.

For Q4 2024, the company reported spending $25.4 million in net cash in operating activities, up from $20.6 million in the same quarter of the previous year, while for the entire year, the amount was $79.1 million. 

Its R&D expenses were $21.8 million for the quarter, a $10.3 million increase from 4Q23 due to the initiation of the MM120 program’s Phase 3 trials, and $65.3 million for the full year. G&A expenses in 2024, meanwhile, declined a bit to $38.6 million due to decreased professional services fees and expenses, which were partially offset by pre-commercialization activities and increased stock-based compensation expense.

Conclusion

We have come a long way since the early days of psilocybin usage, which was mainly limited to recreational and traditional ceremonial uses. Today, it is being actively investigated to treat mental disorders such as anxiety, depression, addiction, substance use, OCD, PTSD, and many others.

Studies show that psilocybin’s potential in treating these mental health issues is no longer a speculation but an actual science. 

Despite showing huge potential in effectively treating these disorders, there’s not much known about the way the popular psychedelic compound works and impacts the human brain.

The latest study has attempted to unravel the mysteries of how this chemical works, down to the specific neurons and receptors. Insights like these effectively help psilocybin become a medical reality that promises a massive leap for mental health therapy.

The discovery that PT neurons and the 5-HT2A receptor play a crucial role in psilocybin’s lasting effects not only brings new clarity to psychedelic research but also paves the path for this drug’s mainstream medicinal usage and a future of more targeted, next-gen treatments.