Fungus Among Us

 Everyone knows that drugs are bad for you. That’s why they’re illegal, right? This outdated idea is facing increased scrutiny, as we’ve already begun to see the prohibition and regulation of some of these substances being reexamined. For example, marijuana is federally recognized as a Schedule 1 drug, a classification that implies it has a high abuse potential and no recognized medicinal value. However, this classification has been challenged by many recent studies that have shown its potential as a treatment option for various conditions ranging from mild nausea to debilitating epilepsy [1]. Another drug in this Schedule 1 category is psilocybin, which was once considered a revolutionary tool in psychotherapy.  This drug isn’t some modern creation synthesized in a lab, it’s a naturally occurring substance found in certain species of mushrooms . The ritual consumption of these mushrooms dates back thousands of years in Mexico, where it had been used for both medicinal and spiritual purposes [2]. In the late 1950’s, isolation of the psychoactive psilocybin molecule allowed scientists to evaluate its potential as a treatment option for various mood disorders and alcoholism [3].However, as the war on drugs ramped up, funding for these studies dried out. After a hiatus that spanned multiple decades, research on this promising molecule is finally resuming. Recent studies indicate that psilocybin can be a powerful treatment option for various ailments such as obsessive compulsive disorder (OCD), addiction, and depression. Its ability to produce a “mystical-type experience” is thought to be correlated with its effectiveness, though the cause of this experience is still under investigation [4]. Despite the uncertainty surrounding this phenomenon, the positive therapeutic results of the drug offer hope for a new tool to fight the rising mental health issues and addiction epidemics that lurk below the surface of our society. 

The “mystical-type experience”, also referred to as a quantum change experience, has been considered a major factor in the success of psilocybin in therapeutic applications [5]. While the term can seem a bit vague and appears rather unscientific, what it actually refers to are, “sudden, distinctive, benevolent, and often profoundly meaningful experiences that are said to result in personal transformations that affect a broad range of personal emotions, cognitions and behaviors” [6].  While experiencing it, “users report a breaking down of the distinction between subject and object, alongside a sense of sacredness, of ‘transcending time and space’, and a deeply felt positive mood” [7]. Though these types of experiences have been reported for centuries, scientists have only recently attempted to experimentally induce them using psilocybin. Overall, these efforts have been met with great success. A 2018 study conducted by Dr. Roland Griffiths of Johns Hopkins School of Medicine, involving 75 participants, found that 61% of subjects who were given a high dose of psilocybin with standard support reported having a complete mystical experience compared to only 4% who were given a low dose with standard support [6]. 1 milligram (mg) of psilocybin per 70 kilograms (kg) body weight was considered a low dose, while up to 30 mg per 70 kg was considered a high dose. The support consisted of meeting with trained staff four times before psilocybin sessions, followed by another meeting the day after their session. During the actual psilocybin sessions, participants were administered a pill containing psilocybin. They were then encouraged to lie down on a couch and wear an eye mask as well as headphones playing a mix of classical and world music. 

While these experiences can often be very spiritual in nature, scientists have worked to pinpoint a neurological and pharmacological explanation. Initial research suggests these experiences are primarily mediated through the 5-HT2A serotonin receptor, where psilocybin acts as a pharmacological agonist. As an agonist, psilocybin binds and activates the receptor, which in turn sets off a series of cascading events, the most noticeable of which being the altered activity of a group of brain regions known as the default mode network (DMN). In particular, neuronal networks in the prefrontal cortex show enhanced activity. This enhanced activity is the result of the activated 5-HT2A  receptor causing an increase in the release of the central nervous system’s major excitatory neurotransmitter, glutamate. The glutamate is released in an asynchronous manner which results in cortical networks becoming disorganized and desegregated [7]. The breakdown within and between these cortical networks is what is believed to be behind the effects of psilocybin, including the mystical experience.

Understanding the neurological pathway of psilocybin is especially relevant for the treatment of obsessive compulsive disorder (OCD). OCD is a psychological disorder that involves anxiety-inducing obsessions that prompt compulsory behaviors. These symptoms lead to a significant decrease in quality of life for the patient [8]. Our understanding of OCD neuropharmacology has improved in recent years, with research demonstrating disruptions in serotonergic, dopaminergic, and glutaminergic neurotransmission [7]. The cascade of neurological effects induced by psilocybin involves both serotonin and glutamate, which suggests it could be a potential pharmacological treatment option. 

Dr. Moreno, from the University of Arizona College of Medicine, found that one dose of psilocybin could result in a marked decrease in OCD symptoms for patients suffering from the disorder. Findings from this study indicated that time after psilocybin ingestion, but not the dosage, had a significant effect on treatment performance [9]. This suggests that OCD symptoms were significantly reduced regardless of the dose of psilocybin administered. While the effects of treatment wore off after a few days, these are still very positive findings. Traditional OCD medications are unreliable and can induce many negative side effects such as drowsiness, nausea, insomnia, nervousness, and dizziness [10]. Dr. Moreno’s research suggests psilocybin could be an effective medication that doesn’t require daily use or involve harsh side effects, potentially making it a better alternative to current treatment options.  

  In addition to clinical studies, preclinical models of OCD have also demonstrated the therapeutic efficacy of psilocybin. Animal models are one example of this. These models involve marble-burying behavior, which is a symptom of OCD in mouse models. Administration of P. argentipes, a mushroom that naturally produces psilocybin, resulted in a significant reduction in marble burying behavior in mice without negatively impacting motor movement [11]. Though not as compelling as experimental research, numerous anecdotal case reports have also indicated the effectiveness of psilocybin as a way to manage symptoms of OCD. One patient had reported taking numerous medications as well as attending therapy with no alleviation of his OCD symptoms [12]. He then began self-administering psilocybin, via consumption of mushrooms that contained the psychoactive molecule, every three weeks. The patient indicated that the psilocybin treatment managed to keep him symptom-free between doses [12]. While this is just one individual, there may be others who can also benefit from treatment with psilocybin.

Another area that psilocybin has shown promising results in is the treatment of addiction. The 5- HT2A serotonin receptor, which psilocybin acts as a pharmacological agonist on, is involved in the modulation of dopamine release. Dopamine is a neurotransmitter in the mesolimbic reward pathway of the brain and plays a role in substance use disorders (SUDs) [13]. The connection between psilocybin and the reward pathway of addiction implies it could be used as a potential treatment option for the dependence to various substances. Research has already indicated its effectiveness at treating nicotine addiction.

A study by Dr. Johnson of Johns Hopkins School of Medicine found that 60% of patients treated with psilocybin were biologically confirmed as smoking abstinent thirty months past their target quit date [14]. Another study out of Johns Hopkins found that 80% of tobacco users treated with psilocybin were biologically proven to be abstinent at 6 months. Of those who remained abstinent, 58% reportedly experienced one or more complete mystical experiences during their psilocybin sessions, suggesting that this phenomenon could impact the efficacy of the treatment [15]. That being said, both of these studies are limited by their sample size of 15 participants each. While it is hard to draw strong conclusions from such small data sets, the results offer some hope in the treatment of SUDs. 

The success in the treatment of tobacco addiction led to the exploration of psilocybin’s effectiveness at treating dependence on other substances as well. A pilot study demonstrated that both percentage of drinking days and percentage of heavy drinking days were significantly reduced in alcohol-dependent patients after treatment with psilocybin [13]. While this is just a pilot study, the results are promising and warrant further investigation.

Similar to addiction, psilocybin’s effects on the 5- HT2A serotonin receptor suggest great potential in the treatment of depression. Traditional depression medications (TCAs, SNRIs, SSRIs) rely on blocking the reuptake of serotonin to increase the amount of the neurotransmitter that can bind to the receptor. Psilocybin bypasses this by directly binding to the 5- HT2A serotonin receptor [16]. Recent studies have shown this to be an effective method of treating depression. One study that demonstrated this was done by Dr. Ross of NYU School of Medicine. It involved 29 patients with depression due to life-threatening cancer. The research showed that after 7 weeks, 83% of depressed patients treated with psilocybin met the criteria for an antidepressant response, compared to just 14% of the control. Statistically significant improvements were maintained even at the 6.5 month follow up [17]. The mystical-experience induced by psilocybin is a strong predictor of these positive long term results in warding off symptoms of depression [16]. Compared to traditional antidepressants which can bring about many unwanted side effects including nausea, weight gain, insomnia, constipation, fatigue, loss of sexual drive, and suicidality, the wider therapeutic index of psilocybin makes it a promising alternative for long-term treatment [18].

While psilocybin can have lasting effects, it isn’t just useful as a long-term treatment option. One psilocybin session can have immediate positive results.  A study out of the Imperial College of London found that suicidality scores were significantly reduced for up to two weeks following a psilocybin session [19]. This acute symptom management could provide enough time for a patient to seek further help and save their life. 

These studies have the potential to usher in the beginning of a new age of medicine. An age where we move beyond the traditional methods pushed by major pharmaceutical corporations and explore other, possibly more natural, treatment options. As mental health problems and addiction rates continue to increase despite the use of traditional medications, it is time to seriously consider psilocybin as one of those options. Psilocybin has the ability to radically alter a patient’s mental state and lead to lasting positive changes. This therapeutic effect can be achieved without the adverse effects associated with pharmacological treatments currently in use for mental health disorders. Not only that, but psilocybin is generally well tolerated and has very low dependence potential [20]. 

This is starting to be recognized, as Oregon and numerous cities in other states around the country have begun to decriminalize the drug. Loosening regulations could bring about a psychedelic renaissance with increased research and access to treatment. This can lead to a happier, healthier world - one where psilocybin is not only used to treat a wide array of psychological disorders, but also used to increase overall wellbeing and life satisfaction, even in healthy individuals.

References

1. Simonian, J., Varanasi, S., Richards, G., Nguyen, A., Diaz-Fong, J., & Le, J. (2020). A critical narrative review of medical cannabis in pediatrics beyond epilepsy, part III: chemotherapy-induced nausea and vomiting and inflammatory bowel disease. Pediatric Medicine, 3. doi:10.21037/pm-20-70

2. Tylš, F., Páleníček, T., & Horáček, J. (2014). Psilocybin—Summary of knowledge and new perspectives. European Neuropsychopharmacology, 24(3), 342–356. https://doi-org.libproxy.temple.edu/10.1016/j.euroneuro.2013.12.006

3. Carhart-Harris, R. L., & Goodwin, G. M. (2017). The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 42(11), 2105–2113. https://doi.org/10.1038/npp.2017.84

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5. Johnson, M.W., Griffiths, R.R. Potential Therapeutic Effects of Psilocybin. Neurotherapeutics 14, 734–740 (2017). https://doi.org/10.1007/s13311-017-0542-y

6. Griffiths, R. R., Johnson, M. W., Richards, W. A., Richards, B. D., Jesse, R., MacLean, K. A., Barrett, F. S., Cosimano, M. P., & Klinedinst, M. A. (2018). Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial attitudes and behaviors. Journal of psychopharmacology (Oxford, England), 32(1), 49–69. https://doi.org/10.1177/0269881117731279

7. Jacobs, E. (2020). A potential role for psilocybin in the treatment of obsessive-compulsive disorder, Journal of Psychedelic Studies, 4(2), 77-87. Retrieved Feb 15, 2021, from https://akjournals.com/view/journals/2054/4/2/article-p77.xml

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11. Matsushima, Y., Shirota, O., Kikura-Hanajiri, R., Goda, Y., & Eguchi, F. (2009). Effects of Psilocybe argentipes on marble-burying behavior in mice. Bioscience, biotechnology, and biochemistry, 73(8), 1866–1868. https://doi.org/10.1271/bbb.90095

12. Wilcox, J. A. (2014). Psilocybin and obsessive compulsive disorder. Journal of Psychoactive Drugs, 46(5), 393–395. https://doi-org.libproxy.temple.edu/10.1080/02791072.2014.963754

13. de Veen, B. T., Schellekens, A. F., Verheij, M. M., & Homberg, J. R. (2017). Psilocybin for treating substance use disorders?. Expert review of neurotherapeutics, 17(2), 203–212. https://doi.org/10.1080/14737175.2016.1220834

14. Johnson, M. W., Garcia-Romeu, A., & Griffiths, R. R. (2017). Long-term follow-up of psilocybin-facilitated smoking cessation. The American journal of drug and alcohol abuse, 43(1), 55–60. https://doi.org/10.3109/00952990.2016.1170135

15. Garcia-Romeu, A., Griffiths, R. R., & Johnson, M. W. (2014). Psilocybin-occasioned mystical experiences in the treatment of tobacco addiction. Current drug abuse reviews, 7(3), 157–164. https://doi.org/10.2174/1874473708666150107121331

16. Roseman, L., Nutt, D. J., & Carhart-Harris, R. L. (2018). Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression. Frontiers in pharmacology, 8, 974. https://doi.org/10.3389/fphar.2017.00974

17. Ross, S., Bossis, A., Guss, J., Agin-Liebes, G., Malone, T., Cohen, B., Mennenga, S. E., Belser, A., Kalliontzi, K., Babb, J., Su, Z., Corby, P., & Schmidt, B. L. (2016). Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. Journal of psychopharmacology (Oxford, England), 30(12), 1165–1180. https://doi.org/10.1177/0269881116675512

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19. Carhart-Harris, R. L., Bolstridge, M., Day, C., Rucker, J., Watts, R., Erritzoe, D. E., Kaelen, M., Giribaldi, B., Bloomfield, M., Pilling, S., Rickard, J. A., Forbes, B., Feilding, A., Taylor, D., Curran, H. V., & Nutt, D. J. (2018). Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology, 235(2), 399–408. https://doi.org/10.1007/s00213-017-4771-x

20. Daniel, J., & Haberman, M. (2018). Clinical potential of psilocybin as a treatment for mental health conditions. The mental health clinician, 7(1), 24–28. https://doi.org/10.9740/mhc.2017.01.024