Randall D. Ordovich Clarkson, MD
May 6, 2022
Introduction: A Brief History of Psilocybin
Mind-altering substances have been used in ancient shamanic practice for thousands of years, merging spiritualism with medicine (Carhart-Harris et al., 2016). In terms of naturally occurring psychedelic substances, there are no more powerful psychoactive compounds than #psilocybin, the active psychoactive compound in hallucinogenic mushrooms. The history of psilocybin use in the Americas was first recorded in the Aztec Indians of South America who referred to psilocybin mushrooms as #Teonanácatl or “God’s #mushroom” (Nichols, 2020). During his journey to #Mexico and 1529, Spanish Franciscan friar Bernardino de Sahagún conducted ethnographic research in the New World, subsequently publishing his 2500 page Florentine Codex (Nichols, 2020). Throughout the Florentine Codex, Sahagún makes several references to Teonanácatl (Nichols, 2020). Unfortunately, little information survived this period due in part to the fact that Spanish conquistadors destroyed most records and artifacts of these civilizations; thus, information of how mushrooms were used remained a mystery for roughly half a millennia (Matsushima et al., 2009)
The modern rediscovery is a very interesting story. The naturally occurring origin of Teonanácatl was an enormous point of controversy among academics, historians, and botanists (Nichols, 2020). This changed, however, when Harvard botanist Richard Evans Schultes obtained the first viable samples of psilocybin species from Huautla, Mexico in 1938 (Nichols, 2020). These specimens were officially identified as Psilocybe caerulescens, Panacolus campanulatus, and Stropharia cubensis. Because of WWII, further investigations into these psychedelic mushroom species were put on hiatus. Then some 20 years later, Wasson (1957) produced a famous photographic exposé of psilocybin mushrooms in Life Magazine. R. Gordon #Wasson was a banker and amateur mycologist who traveled to Huautla de Jiménez in Oaxaca, Mexico in 1955 with his wife Valentina Pavlovna Wasson (Nichols, 2020). In this trip, Mr. and Mrs. Wasson participated in the psychedelic ritual led by Mazatec curandera Maria Sabina (Wasson, 1957). This trip led to the widespread popularization of psilocybin mushrooms in the culture, writ large.
The history of psilocybin use in the Americas was first recorded in the Aztec Indians of South America who referred to psilocybin mushrooms as Teonanácatl or “God’s mushroom”
Shortly after Life Magazine’s 1957 publication, the famous chemist Albert #Hofmann who discovered #LSD in 1943 at Sandoz Pharmaceuticals was given Psilocybe mexicana for the purpose of bioassaying the compounds in 1958 (Geiger et al., 2018; Nichols, 2020). With the help of his colleagues, he ultimately isolated the psychoactive compound that he named psilocybin through a noteworthy process (Nichols, 2020). Hoffman used paper chromatography, separating the chemical constituents of the mushroom into distinct bands, which were then ingested by different members of the research team in order to identify the psychoactive fractions (Nichols, 2020). This was indeed a brilliant moment in psychedelic scientific research! The final molecular synthesis of psilocybin was as follows: 3-[2-(dimethylamino)-ethyl]1H-indol-4-ol dihydrogen phosphate MW 248.248, mp 224 degrees C (Nichols, 2020). This and its dephosphorolated counterpart, psilocin, was also isolated and named by Hofmann (Nichols, 2020). Psilocin is not only the psychoactive metabolite of psilocybin post-ingestion, but is also highly unstable, insoluble in water, and decomposes readily at room temperature (Nichols, 2020).
Throughout the 1960s and 70s, clinical research in psychiatry and psychotherapy found that psilocybin was powerful in its ability to create altered states of consciousness, providing patients with a profound #mystical experience. However, these drugs were classified as Schedule I controlled substances, putting a halt on further clinical research. Since the mid-1990s, however, there has been a resurgence of interest in both psilocybin and psychedelic research. In this paper, we will discuss the spiritual and clinical implications of psilocybin, particularly in its use as a potential #psychotherapeutic.
Psychopharmacology of Psilocybin
Psilocybin (PY, 4-phosphoryloxy-N,N-dimethyltryptamine) is an indole-based plant alkaloid naturally produced as a secondary metabolite in various species of psychoactive mushrooms (Carhart-Harris et al., 2016; Nichols, 2020). Psilocybin shares similar characteristics with other hallucinogenic indolealkylamines (IAAs), with structures resembling endogenous #serotonin, #melatonin, as well as N,N-dimethyltryptamine (#DMT) (Geiger et al., 2018). All of these compounds are derived from the precursor tryptamine, which in turn is the indolamine metabolite of the essential amino acid tryptophan (Geiger et al., 2018). The similarities in chemical makeup of these compounds are critical in their neurophysiologic effects. For instance, psilocybin contains a section identical to DMT, one of the most powerful known psychedelic substances (Carbonaro & Gatch, 2016). DMT is the key psychoactive ingredient in several compounds including ayahuasca, hoasca, and yagé that have been used in South American #shamanic ceremonies for centuries (Carbonaro & Gatch, 2016). The endogenous role of DMT is still unknown, though when exogenously consumed in high doses, results in altered states of consciousness with religious and spiritual overtones (Carbonaro & Gatch, 2016). Similarly, when ingested, psilocybin elicits similar effects through its ability in modulating the serotonergic system.
Psilocybin shares similar characteristics with other hallucinogenic indolealkylamines (IAAs), with structures resembling endogenous serotonin, melatonin, as well as N,N-dimethyltryptamine (DMT)
The primary psychopharmacological activity takes place at cortical serotonin 5-HT2A receptors found predominantly at apical dendrites of cortical pyramidal cells (Carhart-Harris et al., 2016; Nichols, 2020). Regions mostly activated include frontomedial and frontolateral cortex, anterior cingulate, and temporomedial cortex (Nichols, 2020). Psilocybin acts as a prodrug and is rapidly dephosphorylated to psilocin, the psychoactive compound, through the enzyme alkaline phosphatase (Nichols, 2020). Psilocin then acts as an agonist on 5-HT2A receptors, resulting in its psychopharmacological effects. According to Nichols (2020), to achieve its effect, dosing varies between 4–8 mg of psilocybin, which is equivalent to a 2 g dried quantity of Psilocybe mexicana. Upon the onset of action, psilocybin provides a psychedelic state lasting between 4-6 hours (Nichols, 2020).
Psilocybin’s Current Trends and Issues
Since the 1990s, the federal government began to relax restrictions to study classical psychedelics in academic medical settings (Erritzoe et al., 2018). The reasons for the resurgence of psychedelic research is due in large part to the safety and efficacy of psilocybin in the treatment of several conditions, as well as the hard work and effort of organizations such as the Multidisciplinary Association for Psychedelic Studies (#MAPS), to be discussed further below. As of 1996, there have been 112 reports on the use of psilocybin in treatment for depression, anxiety, and substance use disorders (Geiger et al., 2018; Nichols, 2020).
One groundbreaking study was published in the Lancet to investigate the feasibility, safety, and efficacy of psilocybin in the treatment of unipolar treatment-resistant #depression (#TRD) (Carhart-Harris et al., 2016). Carhart-Harris et al. (2016) found that psilocybin was well tolerated with no significant adverse reactions asides from anxiety and transient confusion, nausea, and headache. The study found that depressive symptoms were significantly reduced at one week (67% of participants) and at three months (58% of participants). A follow-up study at six months found that improvements to depressive symptoms persisted (Carhart-Harris et al., 2017).
The reason that psilocybin is so effective at treating depression is because of its effects at modulating 5-HT2A receptors, the same target of traditional anti-depressants such as Selective Serotonin Reuptake Inhibitors (#SSRIs). These traditional antidepressant treatment helps to normalize hyperactivity in the medial prefrontal cortex, which are similar effects found with administering psilocybin (Carhart-Harris et al., 2016). Furthermore, regarding research for the treatment of major depressive disorder (#MDD) as well as TRD, the FDA gave psilocybin a breakthrough therapy designation in October of 2018 (Nichols, 2020; Saplakoglu, 2019). This designation was granted to Compass Pathways, a pharmaceutical company researching the psilocybin’s efficacy in treating MDD patients with a single dose (Saplakoglu, 2019).
The continued research into efficacious ways to treat mood disorders is critical in modern pharmacology. The World Health Organization (WHO) listed depression as the 4th most significant burden of disease globally, affecting countless patients worldwide, resulting in financial externalities of more than $200 billion annually in the United States alone (Carhart-Harris et al.; 2016, Erritzoe et al., 2018). Furthermore, TRD affects 30% of patients with MDD, and 60% of TRD patients experience a complete an absence of remission (Erritzoe et al., 2018). The devastating effects of depression could be assuaged by novel therapies such as psilocybin and other psychedelics that act on the serotonergic system, thereby necessitating continued research in these treatment modalities.
Other conditions have also been subject of speculation and inquiry, most notably the treatment of depression and anxiety in patients diagnosed with both terminal and non-terminal forms of cancer. Johnson & Griffiths (2017) discuss how oral doses of psilocybin of 0.31 to 0.43 mg/kg were enough to result in sustained reduction of depression ratings at both 3- and 6-month follow-up. According to these studies, 80% of patients showed persistent reduction of depression symptoms at 6-month follow-up and 60% of patients showed complete remission (Johnson & Griffiths, 2017). Furthermore, of all participants, those who reported greater subjective mystical-type experiences were more likely to achieve lasting positive results (Johnson & Griffiths, 2017).
In addition to mood disorders and depression, psilocybin has also been used in the treatment of substance use disorders (SUDs) and addiction, with a particular focus on smoking cessation. According to Johnson et al. (2017), 6 million people die from tobacco-related injury annually worldwide, and this figure is expected to rise to approximately 8 million annual deaths by 2030. Needless to say, existing treatment modalities, including nicotine replacement therapy (NRT) have been inadequate at addressing serious tobacco addiction. Johnson et al. (2017) assessed the combination of psilocybin with Cognitive Behavioral Therapy (CBT) and mindfulness training on patients without serious mental illness with a smoking history of roughly 30 pack years. The authors concluded that 67% of participants were abstinent from smoking at 12 months, and at the long-term follow-up, 60% of patients were confirmed as smoking abstinent (Johnson et al., 2017). Another study by Carhart-Harris et al., 2016 discussed how two treatment sessions with psilocybin resulted in abstinence in 80% of long-term heavy tobacco smokers.
These aforementioned results can be held in comparison to traditional controlled studies, with the most effective smoking cessation drugs resulting in less than 31% abstinence at the 12 month follow-up (Johnson et al., 2017). The results of these studies cannot be understated, and other promising areas of psilocybin research also appear promising in the treatment of obsessive-compulsive disorder as well as cluster headaches (Johnson & Griffiths, 2017).
Societal Concerns with Psilocybin and the Psychedelic Counter-Culture
After Hofmann successfully synthesized psilocybin in 1958, #Sandoz Pharmaceuticals began to manufacture #Indocybin™, the synthetic 2mg dose of psilocybin (Johnson & Griffiths, 2017; Johnson et al., 2018; Nichols, 2020). Indocybin™ was being safely used as a psychotherapeutic adjunct until social backlash took place throughout the 1960s, resulting in the ban on possession and marketing of these hallucinogenic substances in 1965 (Johnson & Griffiths, 2017; Johnson et al., 2018; Nichols, 2020).
Alas, psilocybin remains in Schedule I to this day. This is all due to the fact that the media, fueled by largely exaggerated claims of dangers in psychedelic use, single-handedly stifled decades of potential psychedelic research.
Perhaps the greatest detriment to psychedelic research involved Harvard professors Dr. Richard #Alperts and his former colleague, turned hippy psychonaut Dr. Timothy #Leary. Although Leary and Alperts conducted several pivotal studies during their time at Harvard, including their 1962 Marsh Chapel Experiment at Harvard’s Divinity School, Leary took an unproductive path in his promotion of psychedelics, culminating in his 1966 statement to “Turn on, tune in, drop out.” (Pahnke, 1966; Riley et al., 2010). The promotion of ‘turning on’ to psychedelics and meditative practices, ‘tuning in’ to spiritual fulfillment and other aspects of morality and aestheticism, and to finally ‘dropping out’ from the capitalist system in the pursuit of an alternative spiritual life resulted in a powerful swinging 60s counter-culture movement fueled by ‘sex, drugs, and rock and roll’ and an equally powerful reactionary move by mainstream society to put an end to psychedelic drug use (Riley et al., 2010). In that, the FDA has not officially approved psilocybin for therapeutic use since it was placed in Schedule I of the Controlled Substances Act (CSA) in 1970 (Johnson et al., 2018). Alas, psilocybin remains in Schedule I to this day. This is all due to the fact that the media, fueled by largely exaggerated claims of dangers in psychedelic use, single-handedly stifled decades of potential psychedelic research. Thankfully, however, this is now changing and proper research is finally being conducted, including results on both abuse potential and proper psychedelic treatment protocols.
With regard to abuse potential, studies of recreational use find that the physiological effects of psilocybin include increased pulse rate, respiratory rate, and pupil diameter; though, there is no potential for physical dependence or withdrawal (Johnson et al., 2018). Furthermore, in self-administration studies, evidence was sporadic, potentially demonstrating a weak-reinforcement effect, which is unlike other substances of abuse including cocaine with high rates of self-administration (Johnson et al., 2018). Despite these findings, Johnson et al. (2018) conclude the following with regard to abuse potential and scheduling recommendations: “(1) psilocybin has an abuse potential appropriate for CSA scheduling if approved as medicine; (2) psilocybin can provide therapeutic benefits that may support the development of an approvable New Drug Application (NDA) but further studies are required which this review describes; (3) adverse effects of medical psilocybin are manageable when administered according to risk management approaches; and (4) although further study is required, this review suggests that placement in Schedule IV may be appropriate if a psilocybin-containing medicine is approved.”
Conclusively, when used in therapeutic settings, it is important to follow appropriate safety protocols. For instance, it is important to carefully screen candidates and to provide adequate therapeutic support during psilocybin treatment (Carhart-Harris et al., 2016). Another consideration involves patients already on traditional antidepressant treatments. In such cases, serotonergic antidepressants (e.g. SSRIs) may down-regulate the primary receptor target of psilocybin (the 5-HT2A receptor); therefore, patients will need to withdraw from their traditional antidepressant treatments for several days before initiating psilocybin treatment (Carhart-Harris et al., 2016). It is important to note, however, that despite these issues, psilocybin is now considered among drug-experts to be the least harmful and likely to be the ‘most beneficial’ drug of potential misuse (Carhart-Harris et al., 2017).
Psilocybin’s Significance in Psychotherapy
Serotonergic therapeutics have been studied for conditions such as end of life anxiety, treated with LSD-assisted psychotherapy, and concoctions containing DMT such as ayahuasca, being found to be beneficial in reducing refractory depression (Carhart-Harris, 2017). When used as an adjunct in psychotherapy, psilocybin can have significant implications on positive personality changes. In studying the impact that psilocybin has on the big five personality types, Erritzoe et al. (2018) found that #Neuroticism scores significantly decreased while #Extraversion, #Openness, and #Conscientiousness increased following psilocybin therapy. Interestingly, the study found that Agreeableness remained unchanged (Erritzoe et al., 2018). With regard to the parameters of Openness to Experience, psilocybin increased one’s ability to approach new ideas, values, imagination, appreciation for aesthetics, novelty-seeking, as well as heightened creativity (Erritzoe et al., 2018). Incidentally, these effects are also the target goals for traditional antidepressants, demonstrating the similarity of effect in psilocybin treatment (Erritzoe et al., 2018). Furthermore, as discussed above, the effects of psilocybin may be even more profound for the treatment of MDD and TRD than traditional antidepressants. With that, however, it is important to maintain therapeutic protocols when using psilocybin in the clinical setting.
...Neuroticism scores significantly decreased while Extraversion, Openness, and Conscientiousness increased following psilocybin therapy.
As stated by Carhart-Harris (2017), therapeutic sessions must involve a great deal of preparation and support throughout the psychedelic experience for patients. For instance, this may involve physical and emotional presence for the patient before, during, and after the acute psilocybin session (Carhart-Harris, 2017). Empathy is another factor that cannot be neglected. As Carhart-Harris (2017) further argue, additional therapeutic elements must involve active empathetic listening, reassurance, integration, and non-judgmental listening during patient testimony (Carhart-Harris, 2017). If these factors are neglected, then the overall effectiveness of psilocybin treatment may be adversely compromised.
Conclusion with Future Implications for Psilocybin Research
Despite a prohibition period following the categorization of psilocybin as a Schedule 1 controlled substance under the CSA of 1970, today we are experiencing a renaissance of psychedelic research. This is due in large part to the demonstrated safety and efficacy of psilocybin for the treatment of several conditions including but not limited to MDD and TRD. Furthermore, organizations such as MAPS, led by Dr. Rick #Doblin, have been pioneering psychedelic research for post-traumatic stress disorder (PTSD) using 3,4-methylenedioxy-methamphetamine (MDMA) and are currently in phase 3 of their clinical trials (Erritzoe et al., 2018; Ot’alora et al., 2018). Their PTSD research is expected to be complete by 2022 (Erritzoe et al., 2018). Similar to the use of psilocybin in the treatment of MDD and TRD, MDMA when used as an adjunct in psychotherapy can allow for increases in Openness along with a decrease in Neuroticism, allowing patients to be better receptive in treatment for PTSD symptoms (Erritzoe et al., 2018). With increased positive results from current psychedelic research from organizations such as MAPS, Compass Pathways, and researchers such as Dr. Roland Griffiths, Professor in the Departments of Psychiatry and Neurosciences at the Johns Hopkins University School of Medicine, psychedelic therapeutics are gaining a greater degree of public acceptance. Psilocybin is therefore becoming increasingly viable as a treatment option for a variety of challenging psychiatric disorders including MDD, TRD, and PTSD. In conclusion, it is interesting to see how powerful substances such as naturally occurring psychedelics are being brought from a millennia of recorded spiritual and medicinal use, to now be re-integrated into the myriad of modern medicinal approaches for psychotherapeutic treatments.
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