Psilocybin: From Past to Present Gordon Wu MS3 Psychiatry Clerkship The psychedelic compound psilocybinfound in certain species of hallucinogenic

mushrooms, has been a part of human culture for thousands of years[1]. Murals painted onto caves in the Sahara desert dating back to 9000 BC are some of the earliest evidence of human interactions with mushrooms, but perhaps nowhere else were their magical properties more prized than in ancient Mesoamerica where the Aztecs referred to the mushrooms as teonancatl, or "God's flesh"[1] . Psilocybin mushrooms were respected for their potency and reserved for important ceremonies and religious purposes. It took until 1957 for psilocybin mushrooms to enter American societythanks largely to American explorer R. Gordon Wasson, who studied ritual mushroom use in Mazatec villages and wrote a groundbreaking article in Life magazine depicting the immense psychedelic visions experienced [2]. Belonging to the Psilocybe species, chemist Albert Hofmannthe same man who in 1938 created LSD isolated the active compound within the mushroom Psilocybe Mexicana,. The initial discovery of psilocybin was met with optimism and used in psycholytic therapy by psychiatrists. In the 1960s, Timothy Leary at Harvard University championed the used of psychedelics in psychotherapy and brought it to popular culture. However, as recreational abuse of psilocybin flourished, so too did media sensationalism and increasingly restrictive drug laws. Richard Nixon famously called Timothy Leary the most dangerous man in America. [6] In 1966, the United States banned the production and ingestion of hallucinogenic drugs and psilocybin was placed in Schedule 1 category of illegal substances [2]. These restrictions made human research very difficult to continue, and by the early 1970s almost all clinical trials with hallucinogens were put to an end. Currently there has been a newfound scientific interest in the medical benefits of psilocybin. The objective of this paper is to explore the early clinical findings of psilocybin as well as to discuss the current state of psychedelic research. During the early 1960s, doctors Timothy Leary and Richard Alpert headed a series of clinical psilocybin experiments known collectively as the Harvard Psilocybin Project. In one of the more notable experiments, titled the Concord Prison Experiment, 32 inmates at Concord State Prison were administered psilocybin in an attempt to induce lifestyle changes and to reduce crime rates after release [7]. Initial conclusions at 6 months after release from prison showed a 25% incarceration rate for those who underwent psilocybin psychotherapy compared to a 64% re-admission rate observed for the control group [7]. However longer term follow-up statistically showed only a slight improvement in re-incarceration rate between the two groups and was ultimately deemed uncertain. In conclusion, Leary stated the key to long-term reduction in recidivism rates might be the combination of psilocybin-assisted group psychotherapy with a comprehensive follow-up program modeled on Alcoholic Anonymous to support the released prisoners. [5] In another experiment titled the

Marsh Chapel Experiment, their goal was to stimulate and induce religious experiences in religious predisposed subjects using psilocybin as the sole motivation. Graduate divinity students were divided into two groups, the control group receiving niacin and the experimental group given psilocybin [9]. Almost all members of the experimental group reported profound religious experiences, providing proof that psychedelic drugs induce religious experiences [9]. However after a few reckless years, both men found themselves entangled in a controversial situation and under concerns of legitimacy and safety (both Leary and Alpert were famous for self-experimentation) both researchers were fired and the clinical experimentation of psilocybin stopped to a halt. Recently there has been a renewal of scientific research into the potential medical and psychological therapeutic benefits of psilocybin for treating conditions including obsessive-compulsive disorder, cluster headaches, and anxiety related to terminal cancer. A 2010 study on the effects of psilocybin in clinical experiments concluded that although there is a mild risk of undesirable reactions such as dysphoria, anxiety, or panic, the administration of moderate doses of psilocybin to healthy, high-functioning and well-prepared subjects in the context of a carefully monitored research environment is associated with an acceptable level of risk[9] . The authors note, however, that the drugs safety "cannot be generalized to situations in which psilocybin is used recreationally or administered under less controlled conditions. [9]" In 2006, in the first FDA approved clinical study of psilocybin since 1970, Dr. Francisco Moreno at the University of Arizona studied the effects of psilocybin in patients diagnosed with obsessive-compulsive disorder[8]. The study was composed of nine subjects with DSM-IV-defined OCD and no other major psychiatric disorder. Patients were given varying doses of psilocybin over a period of time with obsessivecompulsive symptom severity measured using the Yale-Brown Obsessive Compulsive Scale (YBOCS) and a visual analog scale. Other than one episode of transient hypertension, there were no reported significant adverse effects. Follow up studies showed a significant decrease in OCD symptoms in all subjects during at least one of the sessions (23%-100% decrease in YBOCS score) importantly with the self-reported improvement lasting over 24 hours [9]. That meant the effects of psilocybin for treating symptoms of OCD lasted beyond the initial 6-8 hour high from ingestion of the compound. Dr. Moreno concluded that in a controlled environment, psilocybin is safe to use in subjects with OCD and was associated with acute reductions in OCD symptoms in several subjects [8]. He postulated that this effect may be due to psilocybin acting on the serotonin-2A receptor, resulting in decreased responsiveness to serotonin [8]. Psilocybin has additionally shown relevance for treatment of cluster headaches, known as one of the most painful syndromes known to mankind [12]." In a 2006 study, half of cluster headache patients reported that small doses of psilocybin terminated the attacks. Additionally most of the patients reported extended periods

of relief afterwards, which if proven to be significant, would be a groundbreaking treatment for cluster headaches [12] .There are currently no medications available that have been able to stop and prevent a cluster headache cyclethese preliminary results suggest further study for the use of psilocybin in neurological disorders. Several clinical trials are currently investigating the use of psilocybin in easing the pain and suffering associated with end-stage cancer. Dr Grob at Harbor-UCLA Medical Center performed a pilot study published in 2008 using psilocybin as treatment for anxiety in patients with advanced-stage cancer. The trial was a double-blind study of twelve patients diagnosed with advanced-stage cancer and anxiety treated with a moderate dose (0.2 mg/kg) of psilocybin [13]. Follow-up data gathered using the Beck Depression Inventory, State-Trait Anxiety Inventory and Profile of Mood States was then collected six months after the completion of the treatment sessions. The StateTrait Anxiety Inventory test demonstrated a significant reduction in anxiety at both one and three months after treatment. The Beck Depression Inventory showed an improvement of mood that was statistically significant at six months; the Profile of Mood States identified mood improvement after treatment with psilocybin that was near but did not reach significance [11]. Of note, there were no clinically adverse reactions either physiologically or psychologically for all twelve patients during the psilocybin administration. In conclusion this study established that mild to moderate doses of psilocybin are safe and can markedly reduce anxiety and improve mood for end stage cancer patients [11]. In an interview for the New York Times recently, Dr. Grob stated even with this modest dose, it appears the drug can relieve the angst and fear of the dying [11]. Roland Griffiths is a neuroscientist at Johns Hopkins University with a passion and interest in psychedelic research. In 2008 Dr Griffiths performed experiments using high doses of psilocybin in 18 healthy volunteers. The majority of the volunteers reported a profoundly spiritual experience, and improvements in both mood and attitude that lasted more than a year. After transcendent experiences, people often have much less fear of death, Griffiths says. A year after his psilocybin study that was published in The Journal of Psychopharmacology, 94 percent of his patients said that it was one of the five most meaningful experiences of their lives; 39 percent said that it was the most meaningful experience [14]. Additionally the friends, family and peers of the participants also reported that the psilocybin experience had made the participants calmer, happier and kinder [14]. Dr. David J. Nutt, a psychiatrist at the Imperial College London, has recently published a study in The Proceedings of the National Academy of Sciences, which described using magnetic imaging techniques to scan healthy volunteers dosed on psilocybin in order to capture the transition from normal waking consciousness to the psychedelic state [11]. His research has shown that changes in perception and mood that follow the ingestion of psilocybin are associated with de-activation of regions of the brain that normally work to connect our senses with our perception. In depressed people, Nutt explains, one of those regions, the anterior cingulate cortex, is overactive, and psilocybin may work by turning it off [11]. Researchers did not

expect to find less brain activity with psilocybinit was traditionally thought that psychedelic visions were the result of overactive brain synapses. Instead the current belief is that human consciousness makes sense of the world by filtering out certain stimuli in an attempt to create order and stability in our mind. The visual hallucinations and delirium are not a product of drugs per say; instead they are the sights, sounds and thoughts that are normally suppressedand it is under the influence of psychedelics that this natural barrier is removed and we come to terms with reality. From its ancient spiritual roots with early humans to its modern status as a Schedule I category narcotic, psilocybin has influenced human beings from all cultures and time periods. Although research cooled off after the backlash against the counter culture of the 60s, today the clinical direction for the use of psilocybin in psychotherapy is bright and full of optimism. Dr. Grob at the conclusion of his paper writes, When you make people less afraid to die, then theyre less likely to cling to life at a huge cost to society. After having such a transcendent experience, individuals with terminal illness often show a markedly reduced fear of dying and no longer feel the need to aggressively pursue every last medical intervention available. Instead they become more interested in the quality of their remaining life as well as the quality of their death [11]. In America we spend too much of our healthcare resources prolonging the last few days of life, much of it irresponsible, wasteful and painful. Now, more than ever, we as a society must realize it is time for an honest discussion as to the role of hallucinogens in modern medicine. References:

1. Agurell S, Nilsson JL. (1968). "Biosynthesis of psilocybin. Part II. Incorporation of 2. 3. 4. 5. 6.

labelled tryptamine derivatives". Acta Chemica Scandinavica 22 (4): 1210 8. PMID 5750023. Vollenweider, F. X. Nature Reviews Neuroscience 11, 642-651 (September 2010) ^ a b c "Drug profiles: Hallucinogenic mushrooms". European Monitoring Centre for Drugs and Drug Addiction. 19 September 2011. Retrieved 2011-12-04. ^ Ohenoja E, Jokiranta J, Mkinen T, Kaikkonen A, Airaksinen MM. (1987). "The occurrence of psilocybin and psilocin in Finnish fungi". Journal of Natural Products 50 (4): 7414. http://healthland.time.com/2011/06/16/magic-mushrooms-can-improvepsychological-health-long-term/ Chilton WS, Bigwood J, Jensen RE. (1979). "Psilocin, bufotenine and serotonin: historical and biosynthetic observations". Journal of Psychedelic Drugs 11 (1 2): 619. PMID 392119.

7. Geyer MA. (1998). "Behavioral studies of hallucinogenic drugs in animals:

implications for schizophrenia research".Pharmacopsychiatry 31 (S2): 739.

8. Metzner R. (1998). "Hallucinogenic drugs and plants in psychotherapy and

shamanism". Journal of Psychoactive Drugs 40(4): 33341

9. Strassman R, Wojtowicz S, Luna LE, Frecska E. (2008). Inner Paths to Outer

Space: Journeys to Alien Worlds through Psychedelics and Other Spiritual Technologies. Rochester, Vermont: Park Street Press. p. 147. ISBN 9781594772245.

10. Leary T, Litwin GH, Metzner R. (1963). "Reactions to psilocybin administered in

a supportive environment". Journal of Nervous and Mental Disease 137 (6): 56173.

11. http://www.nytimes.com/2012/04/22/magazine/how-psychedelic-drugs-canhelp-patients-face-death.html?pagewanted=5&_r=1

12. Matsushima Y, Eguchi F, Kikukawa T, Matsuda T. (2009)."Historical overview of

psychoactive mushrooms" (PDF).Inflammation and Regeneration 29 (1): 4758.

13. Johnson MW, Richards WA, Griffiths RR. (2008). "Human hallucinogen research:
guidelines for safety" (PDF). Journal of Psychopharmacology 22 (6): 60320.

14. Keim B. (1 July 2008). "Psilocybin study hints at rebirth of hallucinogen

research". Wired.com. Retrieved 2011-08-08.