Introduction

Enduring clinically significant anxiety and/or depressive symptoms are common in patients with cancer, present in 30–40% of patients in hospital settings (Mitchell et al., 2011). These symptoms are associated with a variety of poor outcomes, including medication non-adherence, increased health care utilization, adverse medical outcomes, decreased quality of life, decreased social function, increased disability, hopelessness, increased pain, increased desire for hastened death, increased rates of suicide, and decreased survival rates (Arrieta et al., 2013; Brown et al., 2003; Jaiswal et al., 2014).

Although pharmacotherapeutic and psychosocial interventions are commonly used to treat anxiety and depression in cancer patients, their efficacy is mixed and limited (Grassi et al., 2014; NCCN, 2014). There are no US Food and Drug Administration approved pharmacotherapies for cancer-related psychological distress, the onset of clinical improvement with anti-depressants is delayed, relapse rates are high, and significant side effects compromise treatment adherence (Freedman, 2010; Li et al., 2012).

With a growing body of evidence linking higher levels of existential/spiritual wellbeing (in cancer patients) with improved quality of life and decreased depression/hopelessness/suicidality (Breitbart et al., 2000; McClain et al., 2003; Nelson et al., 2002), the need to develop effective therapeutic approaches to mitigate this domain of distress has become increasingly recognized within the disciplines of palliative care and psycho-oncology (emphasized within the last two decades by the Institute of Medicine, the World Health Organization, the National Comprehensive Cancer Network, the Joint Commission, the National Consensus Project, and the National Quality Forum) and improvement in these domains is now accepted as an integral component in the care of cancer patients (Puchalski, 2012). A number of manualized existentially oriented psychotherapies have been developed to address these existential/spiritual issues, with some empirical support from clinical trials (Lemay and Wilson, 2008), and several of these approaches were integrated into the therapy platform developed for this study. There are currently no pharmacotherapies or evidence-based combined pharmacological-psychosocial interventions to treat this particular type of distress and unmet clinical need in cancer patients (Breitbart et al., 2010).

Psilocybin, a tryptamine serotoninergic psychedelic, exerts its consciousness altering effects via 5HT2A agonism (Vollenweider and Kometer, 2010). It has a well-established physiological and psychological safety profile in human laboratory and clinical trial research (Johnson et al., 2008), is not known to be addictive and may have anti-addictive properties (Bogenschutz and Johnson, 2016; Krebs and Johansen, 2012; Ross, 2012). It can produce highly salient spiritual/mystical states of consciousness associated with enduring (months to years) positive changes in cognition, affect, behavior, and spirituality (Doblin, 1991; Griffiths et al., 2006, 2008, 2011; Pahnke, 1963). From the early 1960s to the early 1970s, clinical research utilizing the serotoninergic psychedelics, primarily lysergic acid diethylamide (LSD), to treat terminal cancer-related psychological and existential distress was conducted at major academic medical centers in the United States with a total of several hundred participants. These studies occurred largely in the context of open-label trials and showed improvements in the following symptom domains: anxiety, depression, fear of dying, quality of life, and pain (Grob et al., 2013; Grof et al., 1973; Kast, 1966; Kast and Collins, 1964; Pahnke et al., 1969).

Research into the use of hallucinogen treatment models for psycho-spiritual distress in advanced or terminal cancer ceased in the mid 1970s with the passage of the Controlled Substance Act of 1970, which placed all of the serotoninergic psychedelics into schedule I of the US Drug Enforcement Administration’s classification of regulated psychoactive substances.

Building upon hallucinogen research with cancer patients from over four decades ago, two recently published randomized controlled trials (RCTs) with serotoninergic psychedelics to treat cancer-related psychological distress, one using psilocybin in patients with advanced-stage cancer conducted at Harbor-UCLA (Grob et al., 2011) and the other using LSD in patients with a variety of life-threatening illnesses including but not limited to cancer diagnoses (Gasser et al., 2014), suggested acute and sustained treatment benefits. The University of California Los Angeles RCT in patients with advanced-stage cancer included a cohort of 12 participants and reported on the medical and psychiatric safety of administering low-dose psilocybin (0.2 mg/kg) in conjunction with psychotherapy, and revealed trends towards reduced depression and anxiety in the psilocybin group compared to the control condition (Grob et al., 2011).

In the present RCT, the primary hypothesis was that psilocybin, in conjunction with targeted psychotherapy, would significantly decrease anxiety and depression symptoms (compared to an active control, niacin, and the same dose of psychotherapy as the experimental group) in patients with life-threatening cancer diagnoses.