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Integration of psilocybin into palliative care for relief of existential distress

Brenna Knoch
Department of Biology
Lake Forest College
Lake Forest, Illinois 60045


            Palliative care is the necessary care given to patients with life-threatening illnesses. Life-threatening illnesses not only pose the burden of physical pain, but also mental pain. The existential distress that patients feel varies from depression, to anxiety, to spiritual distress. Psilocybin, the psychoactive alkaloid found in hallucinogenic mushrooms, has therapeutic benefits to relieve all three of these types of existential distress (Carhart-Harris et al. 2016; Griffiths et al. 2006; Grob et al. 2016; Ross et al. 2016). Integration of psilocybin into palliative care is a viable option because of its proven therapeutic benefits and relative safety of administration.



            Approximately 90 million people in the United States are suffering from a serious illness and about 7% of them could benefit from palliative care (Center to Advanced Palliative Care 2014). Patients who have been diagnosed with a life threatening disease and are put into palliative care often feel the heavy burden of existential distress. Existential distress is the feelings of hopelessness, anxiety, depression, and loss of the will to live. There are antidepressants and anxiolytics that can help with some parts of existential distress but not all patients respond to these. A viable answer for relief of existential distress is psilocybin. Psilocybin, a psychoactive alkaloid found in hallucinogenic mushrooms, should be considered for integration into palliative care due to its therapeutic and spiritual benefits.



            Before exploring the therapeutic benefits of psilocybin, it is important to explore the background, effects, and pharmacology of psilocybin to show its long-term use and safety.  



            Psilocybin and psilocin are the psychoactive alkaloid found in hallucinogenic mushrooms in the genus, Psilocybe. Hallucinogenic mushrooms are distributed nearly worldwide (Guzmán et al. 1998; Matsushima et al. 2009). The majority of Psilocybe mushrooms are found in or near the Austral hemisphere, mainly in subtropical humid forests (Guzmán et al. 1998). Mexico has 76 neurotropic species of fungi, 44 of which belong to Psilocybe, making it the number one country in the world for psychoactive mushrooms (Guzmán et al. 1998). Psilocybin containing mushrooms show a large variation in potency. Potency depends on the species or variety that is used, their origin, growing conditions, and age (Van Amsterdam et al. 2011). Psilocybin containing mushrooms have been a long history and are widely distributed throughout the world.

The history of psilocybin containing mushrooms is quite extensive.  Prehistorically, humans have been using psychoactive mushrooms for medical, recreational, and religious purposes (Matsushima et al. 2009). The oldest record of psychoactive mushrooms is said to be a painting from 3500 B.C. discovered on the Tassili Plateau, located in the Sahara desert in Southern Algeria (Oss and Oeric 1992). The painting depicts a shaman dancing with a mushroom in his hand (Oss and Oeric 1992). Moreover, the head of the shaman is connected to the mushroom with a broken line, suggesting a mental connection (Oss and Oeric 1992). In 1938, Richard Evan Schultes, a Harvard botanist, investigated the hallucinogenic mushrooms found in Mexico (Oss and Oeric 1992).  The psychoactive mushrooms were brought to the western world in 1957 by a banker named Robert G. Wasson (Oss and Oeric 1992). Wasson had participated in a religious ritual, which included the use of psychoactive mushrooms, two years prior in central Mexico (Oss and Oeric 1992). In 1958, Albert Hoffmann was the first person to isolate psilocybin (Hoffmann et al. 1959). A year later, Hoffmann synthesized it for the first time in history (Hoffmann et al. 1959). Directly after Hoffmann’s synthesis, clinical studies started to occur and continued throughout the 1960s. By the late 60s, psychedelic drug use increased vastly and the government took initiative to control, and ban, its use. Psilocybin was then classified as a Schedule 1 drug in 1970 under the Controlled Substances Act and clinical studies came to a drastic halt (Byrock 2017). Years passed without human studies. The 1990s brought about renewed interest in human research regarding the therapeutic potential of psilocybin (Tyls et al. 2014). Today, psilocybin is one of the most studied hallucinogens due to its relative safety, long duration, and good absorption following oral administration (Hasler et al. 2004). The history of psilocybin is extensive and vouches for its use.


Structure and Chemical Characteristics

            Psilocybin is the active alkaloid found in hallucinogenic mushrooms. Psilocybin (O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine) produces 4 metabolites via active dephosphorylation (Fig.1) (Passie et al. 2002). Psilocin (N,N-dimethyltryptamine) is the main pharmacologically active metabolite produced by psilocybin. Psilocybin and psilocin are the first natural indole metabolites that contain a hydroxyl group in the 4th position, with psilocybin being the first discovered to contain phosphorus (Hoffmann et al. 1959). Structurally, both psilocybin and psilocin mimic serotonin (Fig. 2) (Gambaro et al. 2015).  Psilocybin and psilocin directly impact the mammalian neurological system.

Knoch Fig1


Fig.1. The metabolism of Psilocybin into its 4 metabolites (Passie et al. 2002)


Knoch Fig2


Fig.2. The chemical structure of psilocybin, psilocin, serotonin (Gambaro et al. 2015)


Physical and Somatic effects

            Ingestion of psilocybin containing mushrooms has several physical and somatic effects on the body. Psilocybin produces hallucinogenic effects of which most noteworthy are alteration in perception of time and space, changes in mood, and changes in sensory perception (including colorful visual illusions, complex scenic hallucinations and synesthesias) (Hasler et al. 2004). Physical effects typically begin 20-40 minutes after ingestion, peak at 60-90 minutes (lasting for another 60-120 minutes), and subside during the 4-6 hour period (Hasler et al. 2004). In general, the physiological side effects of psilocybin consumption are not significantly adverse. They can include dizziness, nausea, weakness, muscle aching, shivering, abdominal pain, and dilation of the pupils (Van Amsterdam et al. 2011).  Psilocybin temporarily increases blood pressure and can cause fluctuations in hormone levels. This may pose an issue for users with cardiovascular conditions  (Hasler et al. 2004). There have been no serious physically adverse side effects in clinical studies involving the use of psilocybin (Carhart-Harris et al. 2016; Grob et al. 2011; Hasler et al. 2004; Ross et al. 2016). There is no evidence for physiological or psychological dependence of psilocybin usage (Van Amsterdam et al. 2011). Physiologically, psilocybin use is relatively safe.



            The pharmacology of psilocybin is fairly well understood. Psilocybin is usually ingested orally, per os or smoked (Dinis-Oliveira, 2017:128). After ingestion, psilocin is detectable in the plasma within 20-40 minutes (Passie et al. 2002).  Maximum concentrations of psilocin in the plasma is reached after approximately 100 minutes (Hasler et al. 1997). The half-life of psilocybin in plasma is approximately 160 minutes (Hasler et al. 1997). The half-life of psilocin in plasma is approximately 50 minutes (Hasler et al, 1997; Martin et al. 2013). Psilocin was detected in urine 16 hours after ingestion of dried psilocybin containing mushrooms (Martin et al. 2013).  When ingested, psilocybin is metabolized via rapid dephosphorylation in the intestinal mucosa by non-specific esterase (Tyls et al. 2013).  In the brain, psilocybin directly interacts with serotonergic receptors, with the highest affinity for the 5-HT2A receptor, which is thought to cause sensory hallucinations (Passie et al. 2002). Psilocin has been found to bind to the dopamine receptor D1 (Ray 2010:9). This means that psilocybin is an agonist of both serotonin and dopamine, increasing the activity of the brain just as the endogenous neurotransmitters would. Psilocybin and psilocin bind to many receptors making the effects more widespread.



Palliative Care

            The word “palliative” stems from the Latin word “palliare” meaning to cloak or disguise. In turn, the word “palliative” means to disguise ones pain without dealing with the underlying cause. “Palliative care is the medical specialty focused on improving quality of life for people facing serious illness. The goal of palliative care is to improve quality of life for both the patient and their family” (Center to Advanced Palliative Care, 2014). Palliative care is used to treat a variety of diseases. Among the most common are heart disease, cancer, stroke, diabetes, renal disease, Parkinson’s, and Alzheimer’s. Palliative care can be administered to patients of any age, at any stage in their disease, and alongside curative treatment. According to a systematic review done by Van Mechelen et al., there is a lack of a definition for the palliative care patient. There are ambiguities when it comes to elements of the patient’s health status and the care delivered to them. A clear definition of the palliative care patient needs to be implicated so that future research about palliative care can be more precise (Van Mechelen et al. 2012). Palliative care includes an interdisciplinary team of specialists, including doctors, nurses, social workers, and anyone else who can provide support. It is used within a variety of patients with many different types of diseases. Not only does palliative care aim to relieve physical pain, but also mental pain such as depression and anxiety (Center to Advance Palliative Care, 2014). Palliative care is a necessary medical specialty to aid those with serious illnesses.


Existential Distress in Dying Patients

Dying patients not only deal with physical pain, but also mental pain. Depression is prevalent in terminally ill cancer patients and increases as the cancer advances (Breitbart et al. 1995).  Understanding why patients with a terminal illness want to speed up the dying process is an important element in palliative care. Recently, Breitbart et al. (2000) measured the desire for hastened death in terminally ill cancer patients. They found that depression and hopelessness significantly impacted patients desire for hastened death suggesting that it is necessary to address both of them to improve palliative care (Breitbart et al. 2000). Not only is depression considered prevalent in many studies but there has been an underrecognition and undertreatment of it, especially in patients with terminal illnesses (Davidson and Meltzer-Brody 1999).  Depression is a major mental health disorder that many patients with terminal illnesses endure.

Anxiety is another mental disorder that patients with terminal illnesses face. Research has not explored the prevalence of anxiety in patients with terminal illnesses compared to the prevalence of depression (Chochinov 2000). Although this is true, the prevalence anxiety is found to be very common, reaching up to 70% in some studies (Chochinov 2000). Mitchell et al (2011) suggests that only about 10% of patients with terminal illnesses self-reported anxiety but this is not a reason to eliminate it and solely focus on depression. A possible reason for the under reporting or lack of research done on anxiety in patients with terminal illness could be due to the overlapping of symptoms between anxiety and depression (Pessin et al. 2002). More research needs to be done on anxiety and end of life distress because it plays a significant role in existential distress.

            For a lot of people, religion plays an important part in their lives. In general, religion gives people hope, relief, and comfort. Balboni et al. (2007) examined the adequacy of religious support with end of life treatment preferences and quality of life in advance cancer patients. They found that 88% of participants (N=230) considered religion to be important, and out of those patients nearly half of them reported that their spiritual needs were not being properly met by religious communities and nearly three-fourths reported that their spiritual needs were not being properly met by medical communities  (Balboni et al. 2007). McClain et al. (2003) examined the effects of spiritual well-being on end-of-life despair in terminally-ill cancer patients. They interviewed 160 patients in palliative care with a life expectancy of less than 3 months and found that there were significant correlations between spiritual well-being and desire for hastened death, hopelessness, and suicidal ideation suggesting that spiritual well-being can offer some protection against end-of-life despair (McClain et al. 2003). Lack of spiritual well-being can cause extra despair for terminally-ill patients in palliative care. Increasing spiritual well-being, both in religious and medical communities, can offer relief of existential distress for palliative care patients.


Therapeutic Benefits of Psilocybin

            Psilocybin has a multitude of therapeutic benefits. Since psilocybin is a serotonin receptor agonist, many studies have looked into its therapeutic potential for treating depression. One study completed by Carhart-Harris et al. (2016) tested the effects of psilocybin on patients with moderate-to-severe, unipolar, treatment-resistant major depression in correlation with psychological support. They found that psilocybin use reduced depressive symptoms relative to base line both 1 week and 3 months after high-dose treatment (25mgs of psilocybin) (Carhart-Harris et al. 2016). Ross et al. (2016) backs up these findings with a double-blind, placebo-controlled, crossover trial focused on the effect of psilocybin use to treat depression in patients with life threatening cancer. They found that psilocybin produced immediate, substantial, and sustained improvements in relation to depression which ultimately lead to decreases in cancer-related demoralization and hopelessness (Ross et al. 2016). At the 6.5-moth follow up, single-dose psilocybin treatment still endured anti-depressant effects (Ross et al. 2016). Psilocybin use has been proven to relieve symptoms of treatment-resistant depression and depression associated with end-of-life hardships.

            Psilocybin has also been proven effective for the treatment of anxiety. Grob et al. (2011) completed the first pilot study regarding the use of psilocybin as treatment for anxiety in patients with advanced-stage cancer. This double-blind, placebo-controlled study looked at the effects of a single, moderate dose of psilocybin on anxiety. They established the feasibility and safe administration of moderate doses of psilocybin (Grob et al. 2011). This pilot study sparked the interest in the therapeutic potential of psilocybin to treat anxiety. Two more studies, published in 2016 show that psilocybin can be used to treat anxiety. Ross et al. (2016) concluded that a single-dose of psilocybin can treat both depression and anxiety in patients with life threatening cancer (Ross et al. 2016). Griffiths et al. (2016) explored the effects of psilocybin on depression and anxiety in patients with life-threatening cancer. This randomized, double-blind, cross-over trial found that high doses of psilocybin (22 or 30mg/70kg) produced large decreases in clinician- and self-reported symptoms of depressed mood and anxiety. At the 6-month follow up participants still stated these findings to be true (Griffiths et al. 2016). These studies show that psilocybin use can be an effective therapeutic treatment for anxiety in relation to death and dying.

            Psilocybin can produce transcendental effects which can be a used therapeutically for relief of spiritual distress. Griffiths et al. (2006) studied the effects of psilocybin on mystical-type experiences and their personal meaning and spiritual significance. Thirty hallucinogen-naïve adult volunteers received 2 or 3 sessions of either psilocybin (30mg/ 70kg) or methylphenidate hydrochloride (40mg / 70kg) (Griffiths et al. 2016). Volunteers completed questionnaires immediately after and 2 months after sessions (Griffiths et al. 2016). They found that participants reported substantial personal meaning and spiritual significance in conjunction with the psilocybin use (Griffiths et al. 2006). Psilocybin-induced spiritual experiences and insightfulness are correlated with specific neuronal oscillations of the brain suggesting that there is a direct association of spiritual experiences and a spatiotemporal neuronal mechanism (Kometer et al. 2015). These significant personal and spiritual experience are directly associated with robust activations to the memory in limbic and striatal regions as well as visual and other sensory cortical activations in conjunction with psilocybin use (Carhart-Harris et al. 2012). Psilocybin produces transcendental effects that are therapeutically beneficial to treat spiritual distress.


A Case for the Integration of Psilocybin into Palliative Care  

            As stated above, psilocybin has therapeutic properties that overlap with the existential distress found in many patients in palliative care. It seems almost neglectful to not integrate it, so what is holding physicians and other caretakers back? Psilocybin is still considered a Schedule 1 drug in the United States. The scheduling of psilocybin as a Schedule 1 drug is incorrect. Although psilocybin has hallucinogenic effects, administration has been proven to be safe, both to healthy patients and patients battling life threatening diseases such as cancer. Also, there is no evidence of addiction or substance abuse. The FDA should consider changing the scheduling of psilocybin from Schedule 1 to Schedule 2 so that it can be integrated into palliative care for therapeutic purposes.

            The use of psilocybin for relief of existential distress has been seen in many patients with life-threatening conditions. Taking psilocybin at the end of one’s life may seem to be an odd choice due to its possibilities of having a ‘bad-trip’ (a disturbing experience associated with hallucinogen use), potential for causing anxiety, and provoked feelings of loss of control (Spiegel 2016). Spiegel (2016) examined the effects of psilocybin in women with metastatic breast cancer and found that psilocybin did not cause any of these effects (Spiegel 2016). He even states that the experience felt by the patients is “that facing the ultimate loss of control in a supportive psychotherapeutic setting actually enhances one’s sense of control – it unifies rather than terrifies” (Spiegel 2016). Spiegel also suggests that making use of psilocybin with other psychotherapies that have been proven useful is a viable option (Spiegel 2016). Steven Ross (2011) reports the effects of psilocybin in two patients with cancer, a female and a male, both in their 50’s. In the case of the female, the psilocybin session helped her clear up past issues. Her spiritual distress related to her cancer subsided. In the case of the male, the psilocybin session helped him connect with God and his fear of death completely subsided (Ross 2011). The use of psilocybin in conjunction with psychotherapy has helped many patients deal with the heavy burden of existential distress.

            Although psilocybin seems like the magical answer for the relief of all existential distress for everyone with a terminal illness, there are some things to consider when administering psilocybin. As a general guideline, people with cognitive and emotional conditions associated with diminished or disorganized ego strengths are not good candidates for phamaco-assisted therapy with psychedelics (Byrock 2017). Set and setting, as seen in many religious ceremonies involving psychedelics, are another aspect to take into considerations because non-pharmacological factors can play a role on experiences associated with psychedelic drugs (Hartogsohn 2016; Byrock 2017). A shaman acts as a guide for those participating in the religious ceremonies. It is important to include an experienced individual in psychotherapies involving the use of psilocybin to guide the patient through their experiences and help them interpret them in a meaningful manner. Supervision is also necessary for ensuring the safety of psilocybin (and all psychedelic drugs) (Byrock 2017). As with all drugs, psilocybin use has some considerations that palliative caretakers need to consider before integrating it based on the patient themselves.



 Psilocybin has a long background of use and has recently been a hot topic of interest due to the therapeutic benefits it has in regards to depression, anxiety, and spiritual distress. These 3 aspects of existential distress are all seen in patients within palliative care. The thought of death and dying can place a great burden on an individual which in turn leads them to thoughts of hopelessness and feelings of burden. The integration of psilocybin into palliative care can aid patients with the death and dying process by relieving them of feelings of existential distress. While it seems like a no-brainer for the addition of psilocybin into palliative care, the scheduling of it is holding it back. Also, there are certain aspects to consider when integrating it into specific patients care plan such as set and setting and the mental health of the patient. Even though these things are present, they are not significant enough to stop integration of psilocybin into palliative care. To conclude, the safety and efficacy of psilocybin for the therapeutic purposes for relief of existential distress make it a very viable option for its integration into palliative care.


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