Psilocybin Mushrooms: Ancient Tradition Meets Modern Science
Psilocybin mushrooms, colloquially known as “magic mushrooms,” have been celebrated for thousands of years for their mind-altering properties. Long used in religious and spiritual ceremonies, these fungi contain psilocybin—a psychoactive compound that has captured the attention of modern science for its profound therapeutic potential.
Recent studies suggest that psilocybin may hold promise for tackling some of the most challenging mental health conditions of our time, including treatment-resistant depression, anxiety, and addiction. This article explores the fascinating history, biology, and emerging therapeutic uses of psilocybin mushrooms, as well as the challenges facing their growing acceptance in mainstream medicine.
The Ancient Roots of Psilocybin Use
The use of psilocybin mushrooms dates back thousands of years, particularly in Mesoamerican cultures. Among the Aztecs, the mushrooms were known as teonanácatl, or “flesh of the gods,” and were integral to religious rituals aimed at communicating with the divine. Archeological finds, such as mushroom-shaped artifacts, suggest that these practices were widespread in Central and South America (Guzmán, 2008).
The Spanish conquistadors documented these ceremonies with a mix of curiosity and disdain, but psilocybin largely remained obscure to the Western world until the mid-20th century. In 1957, R. Gordon Wasson, an ethnomycologist, wrote an influential article for Life magazine, detailing his experiences with psilocybin mushrooms in Mexico. Shortly after, Albert Hofmann—best known for synthesizing LSD—successfully isolated and synthesized psilocybin, setting the stage for scientific exploration (Carhart-Harris & Goodwin, 2017).
What Happens in the Brain: The Science Behind the Psychedelic Experience
Psilocybin, also known as 4-phosphoryloxy-N,N-dimethyltryptamine (4-PO-DMT), is a naturally occurring psychedelic prodrug compound produced by more than 200 species of fungi. (wiki)
Psilocybin works by binding to serotonin receptors in the brain, particularly 5-HT2A receptors, disrupting normal neural pathways and creating hyperconnected brain networks. This activity is thought to underpin the altered perceptions, heightened emotional experiences, and feelings of interconnectedness associated with psilocybin use (Carhart-Harris et al., 2012).
Moreover, psilocybin induces neuroplasticity—the brain’s ability to reorganize itself by forming new neural connections. This property is critical in addressing conditions like depression and PTSD, where rigid thought patterns trap individuals in cycles of despair (Ly et al., 2018).
Short-term effects: Users often report vivid sensory enhancements, introspection, and emotional breakthroughs.
A timeline of Research ( taken from https://hopkinspsychedelic.org/achievements )
Regulatory approval to resume psychedelic research (2000)
Psilocybin Produces Enduring Positive Effects (2006,2008)
First research since the 1970s to administer a classic psychedelic (psilocybin) to drug naïve participants. Psilocybin led to profound experiences that 67% of participants rated as among the top 5 most meaningful experiences of their lifetime. The single psilocybin session led to positive changes in moods, attitudes, and behavior for 14 months (and possibly longer), with 64% indicating the experience increased well-being or life-satisfaction. The study also established the safety of high dose psilocybin administration.
Guidelines for Human Psychedelic Research (2008)
First framework for safely shaping the new era of research. This highly cited analysis has provided guidance to researchers and Institutional Review Boards at a growing number of universities which initiated research with psychedelics. This manuscript has helped safely shepherd the growing field of psychedelic research regarding the risks of psychedelic administration and the safeguards which are critical in addressing these risks.
Psilocybin Increases the Personality Domain of Openness (2011)
First study to show that a single administration of psilocybin produced enduring change in personality, which was considered to be a fixed characteristic of individuals that does not change across the lifetime. The personality domain of openness is associated with creativity in the arts and sciences.
Measuring Mystical Experience (2012, 2015)
First validated psychological scale specifically designed for assessing spiritual (mystical) subjective aspects of psychedelic experiences. Measuring mystical experience is important because research with addicted cigarette smokers, distressed cancer patients, and healthy volunteers in non-therapeutic studies have all shown that mystical experience during psilocybin sessions predicts positive behavior change at least 6 months after sessions. Investigating mystical experiences may therefore be critical to further optimizing psychedelic interventions, and understanding how psilocybin affects consciousness.
First-ever NIH grant to study effects of psilocybin on brain function (2016)
The NIH awarded a grant to study the effects psilocybin on brain function. This study utilized fMRI brain imaging techniques to study the effects of psilocybin 1-day before, 1-week after, and 1-month after drug administration, and is the first study of it’s kind to study the long-term effects of psilocybin on brain function.
Measuring Adverse Effects and Challenging Experiences after Psilocybin (2016, 2017)
First validated psychological scale specifically designed for assessing psychologically challenging experiences with psychedelics (what are often called “bad trips” outside of clinical research). Also, first large scale survey study documenting both acute and enduring adverse experiences after taking psilocybin mushrooms in uncontrolled settings. Also in addition, the first study suggesting a relationship between challenging experiences and the personality domain of neuroticism.
Psilocybin Effects in Special Groups - Beginning and Long-Term Meditators and Religious Clergy (2018 and Ongoing)
First studies demonstrating sustained positive effects of psilocybin in several special populations of individuals with interest in spirituality and religious practices.
Enduring effects of psychedelic administration on human brain function (2020)
Findings from the first study to investigate longitudinal effects on brain function after taking psilocybin suggest that psilocybin may increase emotional and brain plasticity. Brain functioning in regions related to emotions and top-down control of emotions were altered, and overall brain connectivity was increased at 1-week and 1-month after psilocybin.
Assessment of pharmacological manipulation of the human claustrum (2020)
The claustrum, once thought to be the seat of consciousness, is a thin sheet of gray matter that reaches out to every other region in the brain. The claustrum has historically been difficult to study, and thus, its function remains mysterious to scientists. Using fMRI brain imaging techniques, CPCR researchers, in collaboration with colleagues at the University of Maryland, observed the activity and connectivity of the claustrum in 15 people after taking psilocybin or placebo. Results showed that both the default mode network and areas of the brain believed to be responsible for setting attention and switching tasks may be disrupted during the effects of psilocybin, and alterations in the claustrum may account for these changes. This study moves us one step closer to understanding the mechanisms of psilocybin in the brain.
Measurement of psychological insight occurring during psychedelic experiences (2020)
Although several measures have been developed to examine acute psychedelic effects (e.g., mystical-type and challenging experiences), no measure assesses acute psychologically insightful experiences that may occur during psychedelic experiences. We recently developed a new measure of psychological insight and tested its psychometric properties in a large international survey study. The measure demonstrated support for several elements of reliability and validity. The measure has the potential to extend the understanding of the acute and enduring effects of psychedelics. Τherapeutic potential: Beyond the immediate experience, psilocybin’s effects on neural pathways may foster long-term psychological healing.
Optimal dosing for psilocybin pharmacotherapy: Considering weight-adjusted and fixed dosing approaches (2021)
We analyzed acute subjective drug effects (mystical, challenging, and intensity) associated with therapeutic outcomes from ten previous studies (total N=288) in which psilocybin was administered in the range 20 to 30mg/70kg (inclusive). Analyses examined the relationships between demographic variables including body weight and subjective effects in participants receiving 20 mg/70 kg (n = 120), participants receiving 30mg/70kg (n=182), and participants whose weight-adjusted dose was about 25mg (to approximate the fixed dose that is currently being evaluated in registration trials for major depressive disorder) (n=103). No significant associations were found between subjective effects and demographic variables including body weight or sex. Across a wide range of body weights (49 to 113kg) the present results showed no evidence that body weight affected subjective effects of psilocybin. These results suggest that the convenience and lower cost of administering psilocybin as a fixed dose outweigh any potential advantage of weight-adjusted dosing.
Psilocybin’s Therapeutic Renaissance
After decades of prohibition, psilocybin is now at the forefront of a “psychedelic renaissance.” Rigorous studies have demonstrated its potential to alleviate mental health challenges where traditional treatments fall short.
Depression
Several landmark trials highlight psilocybin’s effectiveness in treating depression:
A 2016 study in patients with treatment-resistant depression found that two doses of psilocybin produced significant improvements in symptoms, lasting up to six months (Carhart-Harris et al., 2016).
Clinical response and remission of depression after psilocybin therapy (2020)
We completed the first randomized controlled trial testing the efficacy of psilocybin therapy for depression among 24 adults. Findings showed that participants who received immediate psilocybin-assisted therapy compared with delayed treatment showed improvement in blinded clinician rater–assessed depression severity and in self-reported secondary outcomes through the 1-month follow-up. In the overall sample, 71% at 1 month had a clinically significant response to the intervention, and 54% at 1 month were in remission. Findings suggest that psilocybin with therapy is efficacious in treating MDD, thus extending the results of previous studies of this intervention in patients with cancer and depression and of a nonrandomized study in patients with treatment-resistant depression.
A 2021 randomized trial showed psilocybin outperformed escitalopram, a commonly prescribed antidepressant, offering faster and more profound relief (Carhart-Harris et al., 2021).
Palliative Effects of Psilocybin Treatment in Cancer Patients (2016)
Largest and most rigorous study demonstrating that a single administration of psilocybin produces large and sustained decreases in depression and anxiety in patients with a life-threatening cancer diagnosis. The results of this landmark study is providing the basis for the initiation of registration trials in the United States and Europe seeking approval of psilocybin for medical treatment.
Anxiety
Psilocybin has proven particularly effective for patients facing existential anxiety, such as those with terminal illnesses:
A 2016 trial in cancer patients reported that 80% experienced reduced anxiety and depression six months after a single psilocybin session (Griffiths et al., 2016).
Another study found that the “mystical” experiences induced by psilocybin correlated strongly with long-term reductions in anxiety (Ross et al., 2016).
Addiction
Psilocybin-assisted therapy has shown promise in addressing addiction, with studies reporting high rates of success in smoking cessation and alcohol dependency:
Psychedelic Assisted Smoking Cessation (2014, 2017)
First research since the 1970s using a classic psychedelic (psilocybin) to treat addiction, and the first ever study to examine a psychedelic to treat tobacco/nicotine addiction. The pilot study showed that 80% of participants were biologically verified as smoke free 6 months after psilocybin treatment. These are drastically higher than typical success rates, with the most effective medications showing success rates less than 35%.
In a 2019 study, participants significantly reduced their alcohol intake after psilocybin sessions, with many maintaining sobriety at follow-ups (Bogenschutz et al., 2019).
The Legal Landscape: A Slow March Toward Acceptance
Despite its promise, psilocybin remains a Schedule I substance under U.S. federal law, deemed to have no medical use and a high potential for abuse. Yet, the tide is slowly turning:
Decriminalization: Cities such as Denver, Oakland, and Seattle have deprioritized psilocybin enforcement. Paving the way for Moving Psilocybin Out of Schedule I (2018)
Anticipating the potential that Phase 3 research may confirm the efficacy and safety of psilocybin for one or more medical disorders, the Hopkins team critically reviewed available evidence on the abuse liability of psilocybin, from chemistry to animal models to large scale government surveys, according the structure of the Controlled Substances Act. They concluded that if psilocybin is approved as medicine, placement in Schedule IV may be appropriate with additional FDA mandated risk management provisions.
Therapeutic use: In 2020, Oregon became the first state to legalize psilocybin-assisted therapy, paving the way for regulated use (Agrawal et al., 2022).
Safety and Ethical Considerations
While psilocybin is generally safe when administered in controlled settings, challenges remain. Mild side effects like nausea and transient anxiety are common, but the potential for misuse outside of clinical environments raises concerns (Grob et al., 2011).
Equally pressing are ethical questions about access and commercialization. Will psilocybin therapy become prohibitively expensive, accessible only to the privileged few?"
How do we ensure that psilocybin’s potential is harnessed for the collective good without falling prey to commodification or inequity?
Conclusion
The resurgence of psilocybin research signals a pivotal moment in mental health care. From alleviating depression to helping patients confront existential fears, psilocybin mushrooms offer a glimpse into the future of therapy. However, ensuring equitable access and ethical use will be critical as we navigate this transformative era.
The question now is: How do we democratize the profound benefits of psilocybin while safeguarding against its exploitation?
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