Issue:
114
Page: 38-42
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
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
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Rush JA, ed. Entheogens and the Development of Culture.
Berkeley, CA: North Atlantic Books; 2013.
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