675781

research-article2016
JOP0010.1177/0269881116675781Journal of PsychopharmacologyKelmendi et al.

Commentary

The role of psychedelics in palliative care

reconsidered: A case for psilocybin
Journal of Psychopharmacology
2016, Vol. 30(12) 1212­–1214
© The Author(s) 2016
Benjamin Kelmendi1,2, Philip Corlett2,3, Mohini Ranganathan2,5,6, Reprints and permissions:
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Cyril D’Souza2,3,5,6 and John H Krystal1,2,3,4,5,6 DOI: 10.1177/0269881116675781
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Psychiatric research with classic hallucinogens has enjoyed a to death. In the NYU trial, psilocybin produced rapid, substantial,
resurgence of late. While studies performed in the late 1960s and and enduring reductions in cancer-related anxiety and depres-
early 1970s with lysergic acid diethylamide (LSD) and psilocy- sion, improved quality of life, increased spiritual well-being, and
bin demonstrated therapeutic promise by producing a rapid and improved measures of existential distress, and was associated
sustained reduction in anxiety, improvement in mood, and with improved attitudes toward death. At follow-up at six-and-a-
enhanced quality of life in patients with terminal cancer (Grof, half months, the initial robust clinical effects observed after the
1973), a fuller exploration of their use in palliative medicine was administration of a single dose of psilocybin endured in 60–80%
curtailed by the establishment of a strict federal regulatory envi- of the patients, and when patients were asked (six-and-a-half
ronment. Now, after decades of research inactivity, the potential months post drug administration) to reflect on what they thought
of psychedelics to alleviate the distress associated with a terminal of their psilocybin session, 52% and 70% rated the psilocybin
illness has been significantly advanced by the results of two experience as the singular or top 5 most spiritually significant, or
recent studies investigating the efficacy of psilocybin in the treat- the singular or top 5 most personally meaningful experience of
ment of anxiety and depression in patients with life-threatening their entire lives, respectively, while 87% reported increased life-
cancer. Using double-blind, placebo-controlled, crossover satisfaction or well-being attributed to the experience (Ross
designs, the studies conducted at Johns Hopkins University et al., 2016). The findings that single-dose psilocybin can pro-
(JHU) and New York University (NYU) were methodologically duce acute and sustained improvements in cancer-related anxiety
rigorous and broad in the scope of their outcome variables. and depression is perhaps the most important and novel finding
Both studies demonstrated that a single-dose of psilocybin can of the two studies, and add to and extend the findings of a simi-
produce both an acute and enduring reduction in depression larly designed trial in patients with terminal cancer where a sin-
symptoms, anxiety, and existential distress in patients with life- gle low dose (0.2 mg/kg) of psilocybin showed non-significant
threatening cancer. trends for benefit compared with placebo (Grob et al., 2011).
That the studies replicated one another is a source of confi- In both studies, mediation analysis indicates that the mystical
dence in their findings. However, there were also informative dif- experience was a significant mediator of the effects of psilocybin
ferences between the studies. The group at JHU led by Griffiths dose on therapeutic outcomes. Mystical experience is defined as
et al. investigated the effects of a very low dose (1–3 mg/70 kg, encountering a profound sense of unity, transcendence of time
placebo-like) versus high dose (22 mg/70 kg) of psilocybin and space, deeply felt positive mood, noetic quality (sense of
administered five weeks apart in 51 patients diagnosed with life- understanding), ineffability, transiency, and paradoxicality
threatening cancer and suffering with symptoms of depression infused with a renewed sense of purpose and meaning (Griffiths,
and/or anxiety (Griffiths et al., 2016). The group at NYU led by 2006, 2008, 2011; Grob et al., 2013). Further evidence for the
Ross et al. compared the effect of high-dose psilocybin (0.3 mg/
kg, ~21 mg/ 70 kg) with niacin (used as an “active” control) in 29
1Clinical Neuroscience Division, Department of Veterans Affairs National
patients, and both groups received targeted psychotherapy (Ross
Center for Posttraumatic Stress Disorder, Veterans Affairs Connecticut
et al., 2016). All patients were screened and prepared for the
Healthcare System, West Haven, CT, USA
study intervention through several meetings with staff who estab- 2Departments of Psychiatry, Yale University School of Medicine, New
lished rapport and provided an understanding of the range of Haven, CT, USA
altered states of consciousness that might be encountered during 3Departments of Neuroscience, Yale University School of Medicine, New

their treatment sessions. The psilocybin experience was well tol- Haven, CT, USA
erated by all patients, and there were no serious medical or psy- 4Psychiatry Services, Yale-New Haven Hospital, New Haven, CT, USA
5Schizophrenia and Neuropharmacology Research Group, Veterans
chological adverse events.
Both studies evaluated a broad range of outcome measures, Affairs Connecticut Healthcare System, West Haven, CT, USA
6Abraham Ribicoff Research Facilities, Connecticut Mental Health
including the common measures of anxiety and depression, as
Center, New Haven, CT, USA
well as quality of life, spirituality, and mystical experiences. In
the Griffiths et al. trial, high-dose psilocybin produced large and Corresponding author:
sustained decreases in clinician- and patient-rated measures of Benjamin Kelmendi, Clinical Neuroscience Division, National Center for
depressed mood and anxiety, along with increases in quality of PTSD, 950 Campbell Ave 151E, West Haven, CT 06516, USA.
life, life meaning and optimism, and decreases in anxiety related Email: ben.kelmendi@yale.edu

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Kelmendi et al. 1213

role of the mystical experience and/or higher doses in therapeutic mystical effects by altering the balance between predictions and
outcomes comes from two open-label trials for addiction where prediction errors such that errors are registered inappropriately
the mystical experience was correlated with improved smoking and perceptual inferences become deranged (Corlett et al.,
cessation (Garcia-Romeu et al., 2014) and drinking outcomes 2009). These experiences can gather new learning, expanding
(Bogenschutz et al., 2015). Furthermore, Carhart-Harris et al. the possibility space for future inferences (Corlett et al., 2010).
(2016) recently investigated the safety and efficacy of psilocybin This may be reflected in the significantly elevated trait open-
in treatment-resistant depression, and showed that a higher dose ness, which persists for 14 months following a single infusion
correlated with a better treatment outcome. The association of psilocybin (MacLean et al., 2011). Future work will need to
between psychedelic-induced mystical experience and therapeu- discern how and why these drugs can have psychotomimetic
tic outcome, while not new, requires further exploration, as when effects in some individuals and antidepressant effects in others.
induced under optimal conditions and in a controlled setting, it The environmental setting and individual’s baseline are clearly
could provide a valuable therapeutic intervention for disorders crucial to the effects a psychedelic drug can have (Zinberg,
that are otherwise difficult to treat. 1984). Thus expectations and environments may enhance the
Although not the primary aim of these studies, directionality drug’s potential to foster religious and spiritual experiences. In
of the relationship between the pharmacology of the drug, mysti- his book Heaven and Hell, Aldous Huxley observes, “Many
cal experiences, and clinical outcome remains inconclusive. We schizophrenics have their times of heavenly happiness; but the
do not know for certain whether these mystical experiences are a fact that (unlike the mescaline taker) they do not know when, if
cause, consequence or corollary of the anxiolytic effect or uncon- ever, they will return to the reassuring banality of everyday
strained cognition (see below). For instance, it is possible that experiences causes even heaven to seem appalling.”
mystical experiences associated with psilocybin serve as a meas- These studies have demonstrated a critical advancement in this
ure of adequate drug effects rather than mediating an antidepres- field. Psilocybin may offer a novel and potentially valuable
sant and/or anxiolytic effect. Perhaps future studies could shed approach for addressing the psychological suffering of dying often
some light on this relationship by employing other drugs, such observed in this patient population, particularly given the limited
Salvinorin A and other kappa opioid receptor agonists, capable of efficacy of extant treatments. These studies also raise a number of
producing perceptual alterations and mystical experiences simi- important questions that warrant further research. How necessary
lar to serotonergic hallucinogens but pharmacologically different are the acute psychedelic effects of psilocybin for its antidepres-
(Johnson et al., 2011; Ranganathan et al., 2012). Also intriguing sant and anxiolytic effects? What are the predictors of beneficial
is whether the psychoactive effects of psilocybin influence its effects and adverse effects? Would moderate doses have similar
efficacy through, not yet fully understood, psychological mecha- effects? How specific are the effects? For a single dose of a drug to
nisms that continue to exert their effect well beyond the acute have effects that are still detectable six months later opens a new
pharmacological effects. Rapid alleviation in mood is also era of potential psychopharmacological treatments. But it also
reported with a single administration of ketamine, a dissociative begs the question about what is/are the mechanism/s underlying
anesthetic known to occasion mystical experiences. However, the sustained beneficial clinical effects of psilocybin.
the antidepressant effects are relatively transient and typically
disappear after a week. Moreover, not all the psychotropic Declaration of conflicting interests
substances (e.g., scopolamine and nitrous oxide) that induce dis- The authors declared no potential conflicts of interest with respect to the
sociative and/or mystical experiences produce an acute and research, authorship, and/or publication of this article.
enduring clinical benefit. Is there a differentially unique charac-
teristic about the pharmacology of psilocybin and its enduring Funding
clinical effects compared with other serotonin receptor (5-HT2A) The authors received no financial support for the research, authorship,
agonists such as dimethyltryptamine or dipropyltryptamine? and/or publication of this article.
Imaging studies in healthy controls indicate that psilocybin
decreases blood flow to regions of the brain regions collectively References
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