Psilocybe sp.

Psilocybin Reduces Symptoms of Anxiety and Depression in Patients with Cancer in Two Clinical Trials 
by Connor Yearsley
HerbalGram. 2017; American Botanical Council

In December 2016, two clinical trials that investigated the effects of psilocybin on anxiety and depression in patients with cancer were published simultaneously in a special issue of the Journal of Psychopharmacology. Psilocybin is a natural psychoactive compound that is found in some species of fungi. One study was conducted by a research team led by Stephen Ross, MD, at the New York University (NYU) School of Medicine,1 and the other was conducted by a team led by Roland Griffiths, PhD, at the Johns Hopkins University School of Medicine.2

Clinically significant symptoms of anxiety and/or depression are reportedly present in 30-40% of patients with cancer in hospital settings. These symptoms are associated with various negative effects, including medication non-adherence; increased use of health care services; decreased quality of life and social function; increased disability, hopelessness, and pain; desire for hastened death; increased rates of suicide; and decreased survival rates.1

A growing body of clinical evidence has linked existential and spiritual wellbeing in patients with cancer with improved quality of life and decreased depression, hopelessness, and suicidality. Therefore, those in the disciplines of palliative care and psycho-oncology have increasingly recognized the need to develop effective therapies in this area, especially since treatment with antidepressant pharmaceutical drugs is associated with delayed symptom improvement, high relapse rates, and significant adverse side effects that compromise treatment adherence.1

NYU School of Medicine Study

The purpose of this randomized, double-blind, controlled, crossover study was to investigate the efficacy of a single dose (0.3 mg/kg) of psilocybin (Organix Inc.; Woburn, Massachusetts) compared to a single dose (250 mg) of niacin (vitamin B3, the active control), administered with psychotherapy, to treat clinically significant anxiety or depression in patients with life-threatening cancer. Niacin was chosen to mimic some of the effects of psilocybin (sense of warmth, arousal, tingling sensation, etc.). Patients were randomly assigned to take either psilocybin first (dose one) and then niacin (dose two), or niacin first (dose one) and then psilocybin (dose two). Dose one was administered two to four weeks after baseline assessments, and the crossover occurred seven weeks after dose one, at which time dose two was administered.1

Each dosing session lasted eight hours, during which participants were encouraged to lie comfortably and supine while wearing eye shades and listening to standardized music that was “selected by the research team to temporally match the phenomenologic effects of psilocybin over its course of action.” Furthermore, each participant was encouraged to focus on their internal experience.3

Sixteen participants were randomly assigned to receive psilocybin first. Of those, 14 completed dose one, 12 completed dose two (niacin), and 11 completed the six-month follow-up assessments. Fifteen participants were randomly assigned to receive niacin first. Of those, all 15 completed dose one, 14 completed dose two (psilocybin), and 12 completed the six-month follow-up assessments.1

Most of the study participants were recruited from NYU Langone’s Perlmutter Cancer Center. Eighteen (62%) of the 29 participants who completed dose one had advanced cancers (stage III or IV). Nine (31%) had breast cancer, eight (28%) had reproductive cancers, five (17%) had digestive cancers, four (14%) had leukemia or lymphoma, and three (10%) had some other type of cancer. Most participants were Caucasian (26, or 90%), female (18, or 62%), and reported having some religious faith (15, or 52%). The average age of participants was 56.3 years, with a range of 22 years to 75 years. The two groups did not differ significantly in terms of demographics or clinical characteristics.1

All participants had an anxiety-related diagnosis, with most (26, or 90%) meeting criteria for an adjustment disorder and the rest (three, or 10%) for generalized anxiety disorder (GAD). Before the study, 17 participants (59%) had been treated with conventional antidepressant or anxiolytic medication, but none were taking any psychotropics at the time of study enrollment. In addition, 13 participants (45%) reported no previous history of hallucinogen use.1

There were no serious adverse events (AEs) during the trial from psilocybin or niacin. No pharmacological interventions were needed during either dosing session, no psychiatric hospitalizations were required, no participants abused or became addicted to psilocybin, and there were no cases of prolonged psychosis or hallucinogen persisting perception disorder (HPPD). The most common medical AEs attributable to psilocybin were non-clinically significant increases in blood pressure and heart rate (in 22 participants, or 76%), headaches/migraines (in eight participants, or 28%), and nausea (in four participants, or 14%). The most common psychiatric AEs attributable to psilocybin were transient anxiety (in five participants, or 17%) and transient psychotic-like symptoms (in two participants, or 7%; one case of transient paranoid ideation and one case of transient thought disorder). These are all known AEs of psilocybin, and they were transient and tolerable.1

Primary outcome variables were anxiety and depression assessed using six measures: the Hospital Anxiety and Depression Scale (HADS) self-rated subscales for anxiety (HADS anxiety) and depression (HADS depression), and the total combined score (HADS total); the Beck Depression Inventory (BDI) self-report depression measure; and the Spielberger State-Trait Anxiety Inventory (STAI) self-report measure of state (STAI state) and trait (STAI trait) anxiety. These measures were assessed at baseline (two to four weeks before dose one), one day before dose one, one day after dose one, two weeks after dose one, six weeks after dose one, seven weeks after dose one (one day before dose two), one day after dose two, six weeks after dose two, and 26 weeks after dose two. The total duration of the study was about nine months.1

Participants who received psilocybin first experienced “immediate, substantial, and sustained ... clinical benefits” in all six measures of anxiety and depression symptoms (compared to those who received niacin first) before the crossover that occurred seven weeks after dose one. In addition, those who received psilocybin first experienced significant decreases in all six measures of anxiety and depression compared to baseline immediately after receiving psilocybin. These reductions were significant at each time point, including the final time point at 26 weeks after dose two (niacin), which is equal to about eight months after dose one (psilocybin).1

Before the crossover, those who received niacin first experienced either no significant decreases in any of the six outcome measures compared to baseline or transient decreases that became non-significant before dose two (psilocybin). For five of the six primary outcome measures, those who received niacin first experienced significant decreases in anxiety and depression compared to baseline immediately after receiving dose two (psilocybin), and these statistically significant improvements lasted until the end of the study (26 weeks after dose two).1

Seven weeks after dose one (one day before dose two), 83% of those who received psilocybin first (compared to 14% of those who received niacin first) met criteria for antidepressant response using the BDI self-report measure, and 58% of those who received psilocybin first (compared to 14% of those who received niacin first) met criteria for anxiolytic response using the HADS anxiety self-rated subscale. At the 26-week post-dose two follow-up (after both groups had received psilocybin), antidepressant or anxiolytic response rates were about 60% to 80%.1 

There was a significant improvement (P < 0.05) in attitudes and adaptations towards death, measured using the Death Transcendence Scale (DTS; a self-report measure of positive attitudes and adaptations towards death), in the group that received psilocybin first (assessed at the 26-week post-dose two follow-up) compared to the group that received niacin first (assessed two weeks after dose one).1

At the 26-week post-dose two follow-up, when all participants were asked to reflect on what they thought was their psilocybin session, 52% rated the psilocybin experience as the singular (or in the top five) most spiritually significant experience of their entire lives, and 70% rated it as the singular (or in the top five) most personally meaningful experience of their entire lives. In addition, 87% reported increased life satisfaction or wellbeing because of the experience.1

“Single moderate-dose psilocybin, in conjunction with psychotherapy, produced rapid, robust, and sustained clinical benefits in terms of reduction of anxiety and depression in patients with life-threatening cancer,” the study authors wrote. “This pharmacological finding is novel in psychiatry in terms of a single dose of a medication leading to immediate anti-depressant and anxiolytic effects with enduring (e.g., weeks to months) clinical benefits. Even though it is not possible to attribute causality of the experimental drug (in terms of sustained clinical benefit) after the crossover, the post-crossover data analyses of the two dosing sequences suggest that the clinical benefits, in terms of reduction of cancer-related anxiety and depression, of single-dose psilocybin (in conjunction with psychotherapy) may be sustained for longer than 7 weeks post-dosing, and that they may endure for as long as 8 months post-psilocybin dosing.”1

Some limitations of this study were the small sample size, the decreased generalizability that resulted from most of the participants being Caucasian and female, a study design that limited the interpretation of clinical benefits after the crossover, and the use of a control (niacin) with limited blinding.1

Johns Hopkins University School of Medicine Study

This randomized, double-blind crossover study compared the effects of a single, very low, placebo-like dose (1 or 3 mg/70 kg [about 0.01 or 0.04 mg/kg]) of psilocybin to the effects of a single high dose (22 or 30 mg/70 kg [about 0.3 or 0.4 mg/kg]) of psilocybin on measures of depressed mood, anxiety, and quality of life, in addition to measures of short-term and enduring changes in attitudes and behavior in patients with cancer. Patients were randomly assigned to take either the low dose first (dose one) and then the high dose (dose two), or the high dose first (dose one) and then the low dose (dose two). Dose one was administered about one month (on average) after baseline assessments, and the crossover occurred about five weeks after dose one, at which time dose two was administered.2

The study authors decreased the low dose from 3 mg/70 kg to 1 mg/70 kg after 12 participants because of concerns that 3 mg/70 kg might not adequately serve as an inactive placebo. In addition, they decreased the high dose from 30 mg/70 kg to 22 mg/70 kg because two of the first three participants to receive 30 mg/70 kg were withdrawn from the study (one for vomiting after administration and one for personal reasons).2

The low dose of psilocybin was compared to the high dose to minimize the expectancy effects that result when a substance produces highly discriminable effects. Instructions given to participants and study monitors also minimized expectancy effects.2

Participants were encouraged to lie down on the couch, use an eye mask, and listen to a music program, which was the same for all participants. In addition, participants were encouraged to focus on their inner experiences.2

Twenty-seven participants were randomly assigned to receive the low dose first. Of those, 25 completed dose one, 24 completed dose two (the high dose), and 22 completed the six-month follow-up assessments. Twenty-nine participants were randomly assigned to receive the high dose first. Of those, 26 completed dose one, 25 completed dose two (the low dose), and 24 completed the six-month follow-up assessments.2

Participants were recruited through flyers, the internet, and physician referral. Of the 51 participants who completed dose one, 35% had the possibility of cancer relapse, 37% had recurrent/metastatic cancer with more than two years of anticipated survival, and 27% had recurrent/metastatic cancer with less than two years of anticipated survival. Eighteen (35%) had genitourinary cancers, 13 (25%) had breast cancer, eight (16%) had hematologic malignancies, seven (14%) had upper aerodigestive cancer, four (8%) had gastrointestinal cancer, and one (2%) had some other type of cancer. Most participants (94%) were Caucasian, and 49% were female. The average age of participants was 56.3 years. The two groups did not differ significantly in terms of demographics.2

Fourteen (27%) of the 51 participants who completed dose one had major depressive disorder (MDD), 11 (22%) had a chronic adjustment disorder with anxiety, 11 (22%) had a chronic adjustment disorder with mixed anxiety and depressed mood, five (10%) had dysthymic disorder, five (10%) had GAD, four (8%) had a dual diagnosis of GAD and MDD, and one (2%) had a dual diagnosis of GAD and dysthymic disorder.2

After their cancer diagnoses, 51% of participants had used conventional pharmaceutical antidepressant or anxiolytic medications but had stopped taking these medications before study enrollment. In addition, 45% of participants reported past use of hallucinogens. Participants who reported use of cannabis (Cannabis spp., Cannabaceae) or dronabinol (a synthetic cannabis preparation) were asked to not use these at least 24 hours before dosing sessions.2

Several AEs occurred during the trial, but none were considered serious. For example, 15% of participants in the high-dose session experienced nausea or vomiting. In addition, 21% of participants in the high-dose session and 8% in the low-dose session experienced an episode of physical discomfort (any type), and 32% of participants in the high-dose session and 12% in the low-dose session experienced psychological discomfort (any type). About a quarter (26%) of participants in the high-dose session and 15% in the low-dose session experienced an episode of anxiety. During the high-dose session, one participant had a transient episode of paranoid ideation. There were no cases of HPPD or prolonged psychosis.2

Primary outcome measures were clinician-rated symptoms of depression (measured using the GRID Hamilton Rating Scale for Depression [GRID-HAMD-17]) and anxiety (measured using the Hamilton Anxiety Rating Scale [HAM-A]). These measures were assessed at baseline (about one month before dose one), five weeks after dose one, five weeks after dose two, and about six months after dose two (the six-month follow-up). The total duration of the study was about nine months.2

Five weeks after dose one, 92% of those who received the high dose first showed a clinically significant response on the GRID-HAMD-17 (i.e., a decrease of at least 50% compared to baseline), compared to 32% of those who received the low dose first. At the six-month follow-up, 79% of those who received the high dose first continued to show a clinically significant response using this scale. Similarly, five weeks after dose one, 76% of those who received the high dose first showed a clinically significant response on the HAM-A, compared to 24% of those who received the low dose first. At the six-month follow-up, 83% of those who received the high dose first showed a clinically significant response using this scale.2

Five weeks after dose one, for those who received the high dose first, the rate of symptom remission (i.e., a decrease of at least 50% compared to baseline and a score of 7 or less on GRID-HAMD-17 or HAM-A) was 60% for depression and 52% for anxiety. At the six-month follow-up for the same group, the rate of symptom remission was 71% for depression and 63% for anxiety. At the six-month follow-up for all participants, the overall rate of clinical response was 78% for depression and 83% for anxiety, and the overall rate of symptom remission was 65% for depression and 57% for anxiety.2

Eleven of the 17 outcome measures that were assessed at baseline, five weeks after dose one, five weeks after dose two, and at the six-month follow-up met conservative criteria for demonstrating the efficacy of the high dose of psilocybin. That is, these measures all showed both a significant between-group difference (assessed five weeks after dose one) and a significant difference between the post-dose one and post-dose two assessments in the group that received the low dose first.2

The 11 outcome measures that met these criteria were the following: the GRID-HAMD-17, the BDI self-report depression measure, the HADS depression self-rated subscale, the HAM-A, the STAI trait anxiety self-report measure, the Profile of Mood States (POMS) total mood disturbance subscale (a self-rated dysphoric mood measure), the Brief Symptom Inventory (BSI; self-rated psychiatric symptoms), the McGill Quality of Life (MQOL) self-rated measure of overall quality of life (total score) and meaningful existence (existential subscale), the Life Attitude Profile-Revised (LAP-R) death acceptance self-rated scale, and the Life Orientation Test-Revised (LOT-R) self-rated optimism measure.2

Furthermore, mystical experience scores, measured using the Mystical Experience Questionnaire (MEQ30), assessed immediately after dose one, correlated significantly with 18 of 20 measures that were assessed five weeks after dose one.2
“The data show that psilocybin produced large and significant decreases in clinician-rated and self-rated measures of depression, anxiety or mood disturbance, and increases in measures of quality of life, life meaning, death acceptance, and optimism,” the study authors wrote. “These effects were sustained at six months.”2

In addition, participants attributed positive changes in attitudes about life, self, mood, relationships, and spirituality to the high-dose experience, “with over 80% endorsing moderately or higher increased well-being or life satisfaction,” the authors continued.2

Also according to the authors, “the significant association of mystical-type experience (MEQ30) during [dose one] with most of the enduring changes in therapeutic outcome measures five weeks later is consistent with previous findings showing that such experiences on session days predict long-term positive changes in attitudes, mood, behavior, and spirituality.”2

Conclusion

There has been a relatively recent resurgence of interest in using psychedelic substances, including psilocybin and LSD, for clinical therapeutic purposes. These two trials, which are reportedly the most rigorous trials to date using psilocybin, are part of that resurgence. According to Griffiths et al., this resumption of research has helped establish conditions for safe administration of psilocybin.2 In addition, according to Ross et al., the finding that a single dose of psilocybin can lead to significant antidepressant and anxiolytic benefits that can last weeks, if not months, is novel in psychiatry.1 Despite psilocybin’s Schedule I status, these trials suggest that it may have therapeutic potential for addressing existential distress in patients with cancer, and may also indicate that further trials are warranted.

—Connor Yearsley

Sidebar: About Psilocybin

Psilocybin is an indole alkaloid derived from the monoamine alkaloid tryptamine, which, in turn, is derived from the amino acid tryptophan.4 After ingestion, psilocybin is metabolized to the active compound psilocin, which is also present in psilocybin mushrooms, but in smaller amounts.5 Psilocin is pharmacologically similar to lysergic acid diethylamide (LSD; a semisynthetic derivative of ergotamine, which is produced by the ergot fungus Claviceps purpurea [Clavicipitaceae] and related fungi) and the neurotransmitter serotonin (5-hydroxytryptamine [5-HT]).4,5 It has been shown that activation of the serotonin receptor subtype 5-HT2A is responsible for most of the psychedelic (i.e., consciousness-expanding and hallucinatory) effects of the compound.6

A 1998 review by Guzmán et al. identified 186 fungal species that contain psilocybin and related indoles, or that are likely to contain these substances, with the majority (116, or 62%) of these species belonging to the genus Psilocybe (Hymenogastraceae) and the rest belonging to 12 different fungal genera.7

Human use of psilocybin mushrooms likely dates back thousands of years. Prehistoric murals from Tassili n’Ajjer in the Sahara Desert in southeastern Algeria, which are thought to be between 7,000 and 9,000 years old, may depict Psilocybe mairei. Additionally, a portion of the Selva Pascuala mural, which is located in the municipality of Villar del Humo in Cuenca, Spain, may depict P. hispanica. This portion of the mural may be about 6,000 years old, which makes it the oldest known evidence of psilocybin mushroom use in Europe.8

In Mesoamerica, the native use of hallucinogenic mushrooms dates back to pre-Columbian times. In his multivolume Historia General de las Cosas de Nueva España, Franciscan friar Bernardino de Sahagún (1499-1590) recorded the ritualistic use by the Aztecs of psilocybin mushrooms that they called teonanácatl (which translates approximately to “God’s flesh” in Náhuatl). De Sahagún reportedly wrote that mushroom intoxication gave the Aztecs the ability to seemingly change themselves into animals and have powerful visions during which they heard voices they believed to be from God.9

After participating in a Mazatec ritual in Oaxaca, Mexico, which involved psilocybin mushrooms, the amateur mycologists Robert Gordon Wasson, a vice president of J.P. Morgan and Co., and his wife Valentina published a 1957 article in Life magazine titled “Seeking the Magic Mushroom.” This article sparked widespread interest in psilocybin mushrooms and reportedly inspired some, including Harvard psychologist Timothy Leary, PhD, to study and popularize psilocybin and other entheogens (i.e., substances that produce an unordinary state of consciousness for religious or spiritual purposes; in Greek, entheogen means “generating the divine within”).9

In 1959, Swiss chemist Albert Hoffman (who was the first to synthesize LSD in 1938) isolated the active principle psilocybin from Psilocybe mexicana. In the 1960s and 1970s, hallucinogens, including psilocybin and LSD, were the subjects of multiple studies, but this research stopped for almost three decades after the US Controlled Substances Act of 1970 placed these substances into Schedule I, the most restrictive and punitive schedule. This was done because of concerns about widespread non-medical use of these compounds.1,2

Psilocybin is not known to be addictive and may have anti-addictive properties. It also has a well-established safety profile in human laboratory and clinical trial research. According to Ross et al., since the early 1990s, about 2,000 varying doses of psilocybin have been safely administered to humans in the United States and Europe, in carefully controlled clinical settings.1

Psilocybin mushrooms can induce a sense of exhilaration, hallucinations that include vivid and bright colors and shapes, euphoria, distorted perception of time, and impaired judgment. Stationary objects may appear mobile. In addition, although visual hallucinations are more common, auditory hallucinations can also occur. Hallucinations typically do not last longer than four or five hours.4
 
References

1.   Ross S, Bossis A, Guss J, et al. 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. 2016;30(12):1165-1180. doi: 10.1177/0269881116675512.

2.   Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. Journal of Psychopharmacology. 2016;30(12):1181-1197. doi: 10.1177/0269881116675513.

3.   Supplement to: Ross S, Bossis A, Guss J, et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016;30(12):1165-1180. Available at: journals.sagepub.com/doi/suppl/10.1177/0269881116675512/suppl_file/JOP675512_Appendix.pdf. Accessed April 26, 2017.

4.   Psilocybine. Toxicology Data Network website. Available at: toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+hsdb:@term+@rn+@rel+520-52-5. Accessed April 19, 2017.

5.   Hallucinogenic mushrooms drug profile. European Monitoring Centre for Drugs and Drug Addiction website. Available at: www.emcdda.europa.eu/publications/drug-profiles/mushrooms. Accessed April 19, 2017.

6.   Lee H-M, Roth BL. Hallucinogen actions on human brain revealed. Proceedings of the National Academy of Sciences. 2012;109(6):1820-1821. doi: 10.1073/pnas.1121358109.

7.   Guzmán G, Allen JW, Gartz J. A Worldwide Geographical Distribution of the Neurotropic Fungi, an Analysis and Discussion. Annali del Museo Civico di Rovereto: Sezione: Archeologia, Storia, Scienze Naturali. 1998;14:189-280. Available at: www.museocivico.rovereto.tn.it/UploadDocs/104_art09-Guzman%20&%20C.pdf.

8.   Akers BP, Ruiz JF, Piper A, Ruck CAP. A prehistoric mural in Spain depicting neurotropic Psilocybe mushrooms? Economic Botany. 2011;65(2):121-128. doi:10.1007/s12231-011-9152-5.

9.   Rush JA, ed. Entheogens and the Development of Culture. Berkeley, CA: North Atlantic Books; 2013.
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