Terminology surrounding psychedelic mushrooms has evolved over time, with colloquialisms like "shrooms," "mushies," and "magic mushrooms" becoming increasingly prevalent. However, renowned mycologist Paul Stamets advocates for a more mature discourse, emphasizing that these fungi are not merely recreational substances but possess transformative potential. "We must approach this topic with maturity. Psilocybin mushrooms are not just 'shrooms' or party drugs for the youth," Stamets stated. "They are nonaddictive and have the power to alter lives significantly."

Emerging clinical studies suggest that a single or double dose of psilocybin, administered in a therapeutic context, can induce profound and enduring changes in individuals grappling with major depressive disorder that is unresponsive to conventional antidepressants. This has led the US Food and Drug Administration to classify psilocybin as a groundbreaking therapy, a development Stamets describes as "remarkable."

Psilocybin, which the body metabolizes into psilocin—a compound with psychoactive properties—also shows promise in addressing conditions like cluster headaches, anxiety, anorexia, obsessive-compulsive disorder, and various substance abuse issues. "The evidence is compelling, spanning from depression to PTSD to cluster headaches, which are among the most excruciating conditions I know," noted neurologist Richard Isaacson, who heads the Alzheimer’s Prevention Clinic at Florida Atlantic University's Center for Brain Health. "The safety profile of psychedelics is relatively favorable, and their study in rigorous, double-blind clinical trials excites me. This progression allows us to transition from anecdotal accounts to statistically significant improvements."

Psychedelic substances like psilocybin and LSD enter the brain through the same receptors as serotonin, the body's "feel-good" chemical. Serotonin regulates functions such as sleep, libido, and psychological states including contentment, joy, and optimism. Individuals with depression, anxiety, PTSD, cluster headaches, anorexia, smoking addiction, and substance abuse often have low serotonin levels. Standard treatment involves selective serotonin reuptake inhibitors (SSRIs), which increase serotonin availability to brain cells, but improvements can take weeks, if they occur at all.

In contrast, changes in brain neuron connectivity due to psychedelics like psilocybin and LSD can be observed in the lab "within 30 minutes," according to pharmacologist Brian Roth, a professor at the University of North Carolina at Chapel Hill. "Classic psychedelics significantly affect how brain systems synchronize," explained Matthew Johnson, a professor in psychedelics and consciousness at Johns Hopkins Medicine. "Psilocybin increases connectivity between brain regions that typically communicate poorly, while also reducing communication within local networks that usually interact frequently."

This leads to a "highly disorganized brain," breaking down the usual boundaries between auditory, visual, executive, and self-perception areas, resulting in an "altered state of consciousness," as described by David Nutt, director of the Neuropsychopharmacology Unit at Imperial College London. Nutt suggests that this disorganization is therapeutic: "Depressed individuals are often self-critical and ruminate on negative thoughts. Psychedelics disrupt this pattern, allowing people to see a way out of their depression."

Furthermore, psychedelic drugs are believed to promote the growth of new dendrites in brain neurons, enhancing cell communication. "These substances can increase neuronal outgrowth, branching, and synapses, a process known as neuroplasticity," Nutt said. This is distinct from neurogenesis, the formation of new brain cells from stem cells. Dendrite growth aids in establishing and consolidating new brain circuits, enabling positive pathways, such as those associated with gratitude.

Current thinking suggests that while neuronal outgrowth may not directly contribute to increased brain connectivity, it likely helps individuals maintain insights gained during psilocybin treatment. "You disrupt the brain, perceive things more positively, and then establish those positive circuits through neuroplasticity," Nutt added. "It's a double benefit."

Interestingly, SSRIs also enhance neuroplasticity, but a 2022 double-blind phase 2 randomized controlled trial comparing psilocybin to escitalopram, a conventional SSRI, found that the latter did not increase brain connectivity or well-being as effectively as psilocybin.

While not everyone responds to psychedelic treatment, when it is effective, it can be transformative. "If individuals have fundamentally changed their brain's automatic response to anxiety, depression, or smoking triggers, that's a significant outcome," Johnson emphasized.

The duration of treatment effects varies; some patients given a single psychedelic dose showed improvement up to eight years later, although for most with chronic depression, symptoms often return after four to five months. The approach to such cases remains uncertain, with possibilities including additional doses of psychedelics or SSRIs to maintain mood improvement.

Stamets, who has discovered four new species of psychedelic mushrooms and authored seven books on the subject, advocates for microdosing—consuming small amounts of psilocybin mushrooms multiple times a week to maintain brain health and creativity. A typical microdose is 0.1 to 0.3 grams of dried psilocybin mushrooms, compared to the 25-milligram dose that induces a full psychedelic experience.

Stamets practices microdosing and has explored "stacking," combining a microdose of mushrooms with other substances believed to enhance their effects. His "Stamets Stack" includes niacin (vitamin B3) and the mycelium of Lion's mane mushrooms. Surveys on his website suggest significant benefits from microdosing, although scientific studies have yet to confirm these effects, leaving many researchers skeptical.

Experimental psychologist Harriet de Wit, a professor at the University of Chicago, studied microdosing to address the challenge of blinding participants in scientific research, as the small dose does not produce noticeable effects. Her 2022 study on microdosing LSD found only stimulant-like effects at very low doses, which then diminished.

Nutt suspects that microdosing may affect mood and build resilience or well-being over time but does not believe it can rapidly alleviate depression as macrodosing (a full psychedelic experience) can.

It's important to note that not all hallucinogenic experiences are positive, and nearly every psychedelic study includes therapists to intervene if a trip becomes adverse and to optimize outcomes if the trip is positive. "This is about providing deeper access to one's mental processes for greater insight," Johnson said. "While opinions may differ, it seems clear that therapy is essential to maximize benefits."

There are also side effects beyond adverse trips, with substances like LSD, mescaline, and DMT potentially increasing blood pressure, heart rate, and body temperature. Additionally, individuals seeking psychedelic mushrooms risk ingesting toxic varieties, leading to accidental, fatal poisoning.

Furthermore, not everyone is suitable for psychedelic treatment. Those on SSRIs, with bipolar disorder, schizophrenia, or a family history of psychosis are typically excluded from clinical trials. "If you're predisposed to psychosis, exposure to psychedelics could trigger or cause a psychotic episode," Barnes explained.

For individuals with mental health concerns who are unwilling to undergo a psychedelic experience, scientists like Roth are seeking alternative approaches. Roth's team has identified how psychedelics bind to serotonin receptors and is using this knowledge to discover new compounds. "Our goal is to develop medications that replicate the benefits of psychedelic drugs without the psychedelic experience," Roth said. "Imagine a medication for depression, PTSD, anxiety, or obsessive-compulsive disorder that allows patients to wake up feeling better without side effects. That would be revolutionary."