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. Author manuscript; available in PMC: 2024 Feb 15.
Published in final edited form as: J Affect Disord. 2022 Dec 10;323:592–597. doi: 10.1016/j.jad.2022.11.046

Psilocybin-assisted therapy mediates psycho-social-spiritual change in cancer patients as assessed by the NIH-HEALS

Sarah Shnayder 1, Rezvan Ameli 1,2, Ninet Sinaii 3, Ann Berger 2, Manish Agrawal 1
PMCID: PMC9884542  NIHMSID: NIHMS1859137  PMID: 36513161

Abstract

Background:

While psychedelics have been shown to improve psycho-spiritual well-being, the underlying elements of this change are not well-characterized. The NIH-HEALS posits that psycho-social-spiritual change occurs through the factors of Connection, Reflection & Introspection, and Trust & Acceptance. This study aimed to evaluate the changes in NIH-HEALS scores in a cancer population with major depressive disorder undergoing psilocybin-assisted therapy.

Methods:

In this Phase II, single-center, open label trial, 30 cancer patients with major depressive disorder received a fixed dose of 25 mg of psilocybin. Participants underwent group preparation sessions, simultaneous psilocybin treatment administered in separate rooms, and group integration sessions, along with individual care. The NIH-HEALS, a self-administered, 35-item, measure of psycho-social spiritual healing was completed at baseline and post-treatment at day 1, week 1, week 3, and week 8 following psilocybin therapy.

Results:

NIH-HEALS scores, representing psycho-social-spiritual wellbeing, improved in response to psilocybin treatment (p<0.001). All three factors of the NIH-HEALS (Connection, Reflection & Introspection, and Trust & Acceptance) demonstrated positive change by 12.7%, 7.7%, and 22.4%, respectively. These effects were apparent at all study time points and were sustained up to the last study interval at 8 weeks (p<0.001).

Limitations:

The study lacks a control group, relies on a self-report measure, and uses a relatively small sample size with limited diversity that restricts generalizability.

Conclusions:

Findings suggest that psilocybin-assisted therapy facilitates psycho-social-spiritual growth as measured by the NIH-HEALS and its three factors. This supports the factors of Connection, Reflection & Introspection, and Trust & Acceptance as important elements for psycho-social-spiritual healing in cancer patients, and validates the use of the NIH-HEALS within psychedelic research.

Keywords: psilocybin, cancer, psycho-spiritual, healing, NIH-HEALS

Introduction

A cancer diagnosis can have a devastating effect on physical, psychological, and spiritual well-being (Niedzwiedz et al., 2019; Zare et al., 2019). While extensive focus has been placed on mitigating the physiological impact, recent efforts have aimed to uncover the psycho-spiritual needs of cancer patients (Hatamipour et al., 2015; Astrow et al., 2018). Many cancer patients experience clinical depression and anxiety (Zabora et al., 2001; Mitchell et al., 2011), a debilitating fear of dying, disconnectedness, lack of control, and loss of hope (Coward & Kahn, 2004; Moreno & Stanton, 2013). Yet, traditional pharmacotherapeutics have mixed and limited efficacy in treating cancer-related distress (Li et al., 2012).

Psychedelic therapies such as psilocybin (Griffiths et al., 2016) are among novel therapeutic approaches that have found a renewed relevance in recent years. Throughout history, Indigenous tribes have utilized plant-based hallucinogenic substances for their healing properties. These ceremonies promoted mystical experiences, open-mindedness, and connection with nature and the divine (Carod-Artel, 2015; Nichols, 2020). During the 1960s-1970s, psychedelic research in the United States documented profound effects on psychological health, quality of life, and pain in cancer patients (Kast & Collins, 1964; Kast, 1966; Pahnke, 1969).However, safety concerns were raised in response to widespread non-medical use, and clinical research was halted with the Controlled Substance Act. Since then, conditions for safe administration, proper set and setting, and a code of ethics for psychedelic use have been established (Johnson et al., 2008; Mithoefer, 2017). In more recent clinical trials, psilocybin was found to promote significant and substantial improvements in cancer-related depression, anxiety, existential distress, and orientation towards death (Grob et al., 2011; Griffiths et al., 2016, Ross et al., 2016). While the effects are clear, the mechanistic underpinnings of psychedelic-mediated psycho-spiritual change in cancer patients are less understood.

A recently validated measure, the NIH-HEALS, has been developed based on interviews with patients who experienced positive psychological, social, and spiritual change after being diagnosed with severe and/or life-threatening diseases. Two hundred patients, 80% of whom had diagnoses of cancer, were recruited from the NIH Clinical Center and participated in the validation of the NIH-HEALS. Results showed the measure to have high internal consistency, split-half reliability, and convergent and divergent validity (Ameli et al., 2018). Factor analysis of the NIH-HEALS yielded three primary elements instrumental in psycho-social-spiritual healing: (1) Connection: a sense of interconnectedness; religious, spiritual and interpersonal connectedness; level of connection to a higher power, community, and family; (2) Reflection & Introspection: a sense of meaning, purpose, and gratitude, experience of joy in nature, use of activities that connect mind and body, present moment orientation, and an awareness about the fragility of life; (3) Trust & Acceptance: the ability to let go of resistance, to feel resolved and at peace with one’s circumstances, and to trust that caregivers, friends and family will respond to needs as they arise. These factors are consistent with cancer literature, as higher well-being in cancer patients has been linked to one’s connectedness with others (Lin & Bauer-Wu, 2003), sense of life-meaning (Lin & Bauer-Wu, 2003; Sleight et al., 2021), and acceptance of the diagnosis (Secinti et al., 2019).

The factors of connection, reflection/introspection, and trust/acceptance are also influenced by psychedelic therapy. Subjective reports indicate that psychedelic therapy can improve one’s sense of connection, as participants have described experiences of reduced self-other boundaries (Smigielski et al., 2020), increased nature relatedness (Kettner et al., 2019), and a profound sense of oneness with all (Watts et al., 2017). Psychedelic therapy is also thought to promote introspection by leading one on an exploration of the unconscious, to discover all disavowed aspects of the self and begin a process of attachment repair (Vaid & Walker, 2022)., Lastly, psychedelics may encourage acceptance, as attempts to exert control over a challenging psychedelic experience typically fail while adopting an allowing attitude and letting go provides the intended relief (Wolff et al., 2020). This encounter teaches one to move towards suffering rather than away, transforming habitual avoidance into a growth-inclined attitude (Watts et al., 2017).

We hypothesize that the elements of Connection, Reflection & Introspection, and Trust & Acceptance underlie the psycho-social-spiritual improvements evidenced in psilocybin therapy. Thus, the present study aims to evaluate the changes in NIH-HEALS scores in a cancer population with major depressive disorder following psilocybin-assisted therapy.

Methods

Study Design

This was a Phase II, single-center, fixed dose, open label trial of psilocybin-assisted group therapy in cancer patients with Major Depressive Disorder (MDD). Psychotherapeutic care was provided before, during, and after psilocybin administration to cohorts of 3–4 participants. Supportive therapy included individual and group preparation sessions, simultaneous administration of psilocybin to the cohort, and individual and group integration sessions. This study (NCT04593563) took place in a cancer center in Rockville, Maryland. It was approved by the Advarra Institutional Review Board (IRB), sponsored by Maryland Oncology Hematology, PA., and funded by COMPASS Pathways Ltd., the psilocybin manufacturer.

Participants

Thirty (30) participants were recruited during an 8-month period at the study site and through referrals from specialized psychiatric and oncology services using convenience sampling. Written consent was obtained from each participant prior to the study. Inclusion criteria were: 1) aged ≥ 18 years, 2) Major Depressive Disorder single episode or recurrent without psychotic features according to the DSM-5, 3) Hamilton Depression Rating Scale (HAMD) score ≥ 18 at baseline, and 4) malignant neoplasm based on ICD-10 codes C00-C97. Exclusion criteria were adapted from current standards for psilocybin safety profiles, which include current or past history of psychotic disorders, bipolar disorders borderline personality disorder, or significant suicide risk. Patients tapered psychiatric medications per standard psychedelic research practices in order to participate safely (Johnson et al., 2008). No cancer-related procedures were performed during the study period, but oral cancer medications were continued.

Study Procedure

Cohorts of 3–4 participants completed screening, baseline assessment, treatment, and follow-ups with a total of 8 visits during the 8-week study period (Figure 1). During Visit 1, participants signed an informed consent form and were assessed for their eligibility with the Mini International Neuropsychiatric Interview, Version 7.0.2 (MINI 7.0.2) (Sheehan, 1998), the 17-item Hamilton Depression Rating Scale (HAMD) (Hamilton, 1960), and the Columbia-Suicide Severity Rating Scale (C-SSRS) (Posner et al., 2008). The following information was also obtained during Visit 1: medical history, physical examination, medication use, vital signs, electrocardiogram (ECG), and blood and urine samples. Eligible participants then entered the screening period and were further evaluated with the Euro Quality of Life- 5 Dimensions (EQ-5D-5L), the DSM-5 Anxious Distress Specifier (DADSI), the Quick Inventory of Depressive Symptomatology (QIDS-SR), and the Sheehan Disability Scale (SDS). Clinicians were all licensed with master’s or doctorate degrees and supervised by an experienced psychedelic therapy informed senior clinician.

Figure 1. Study schematic outline.

Figure 1.

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Following the screening phase, participants went through two preparation sessions, psilocybin therapy, and two integration sessions. Safety, efficacy, and exploratory measures were administered at V2 (Baseline), V4 (Day 1), V5 (Week 1), V6 (Week 3), and V7 (Week 8).

Abbreviations: EoS = End of Study; V = Visit

After passing the screening phase, participants met with their assigned therapist for their first preparatory session (V1a). This 2-hour visit was designed to impart information regarding the psilocybin treatment, introduce coping strategies such as breathing exercises, and establish a therapeutic alliance. Visit 2 (Baseline), occurred one day prior to the psilocybin treatment. This visit included the administration of outcome measures and a two-part therapeutic session, with both group and individual components. The group component was guided by a lead therapist, who disseminated psychoeducational material and encouraged interaction among participants. The goal of the group preparation session was to support the development of a relationship among the group members, treatment team, and the designated therapists. Participants also met individually with their assigned therapist to address individual concerns, set intentions for the session, and practice techniques for managing anxiety and supporting experiential engagement.

At Visit 3, participants were administered 25 mg of psilocybin alongside their cohort in individual rooms, supported by their assigned therapist. The therapeutic approach was non-directive and entailed the use of eyeshades and a music program to promote an inner-directed experience. The dominant mode of therapy was active listening and presence. Therapeutic goals were to ensure psychological safety, to maintain each participants attention on the present moment, and to encourage processing of potentially challenging emotional states. Adverse events (AEs) were recorded during the session.

Visits 4 and 5 occurred in a similar two-part therapeutic approach, with group and individual components. The aim of these sessions was to facilitate integration of the psychological material accessed during the psilocybin therapy by exploring these experiences, their significance and meaning, and their impact on participants’ lives. Consistent with self/inner-directed inquiry, therapists did not make interpretations, influence understanding, give advice, or suggest solutions during integration sessions.

The NIH-HEALS was administered at four time points: baseline (V2), week 1 (V5), week 3 (V6), and week 8 (V7) post-treatment.

NIH-HEALS

National Institute of Health, Healing Experiences in All Life Stressors (NIH-HEALS), is a psycho-social-spiritual measure of healing when faced with challenges (Table 1) (Ameli et al., 2018). The NIH-HEALS has strong convergent (r = 0.64, p < 0.0001) and divergent validity (r = −0.34, p < 0.0001). There are 35-items scored using a 5-point Likert scale, with total scores ranging from 35 to 175. It has three factors, namely Connection (e.g., “my situation strengthened my connection to a higher power”), Reflection & Introspection (e.g., “working through thoughts about the possibility of dying brought meaning to my life”), and Trust & Acceptance (e.g., “I accept things that I cannot change”) (Ameli et al., 2018). It is important to note that the NIH-HEALS three factors are not discrete constructs. Rather, they are related concepts that delineate psycho-social-spiritual elements that could contribute to the experience of healing.

Table 1.

Three-Factor, 35-item NIH-HEALS Measure of Psycho-Social-Spiritual Wellbeing

Connection Reflection & Introspection Trust & Acceptance
3. Connection with a higher power is important to me 4. I gain awareness from self-reflection 1. I am content with my life
12. I survived difficult circumstances because of a higher power 5. I enjoy activities that involve both the mind & body 2. I have a sense of purpose in my life
13. My situation strengthened my connection to a higher power 9. Working through thoughts about dying brought meaning to my life 6. I feel isolated
14. My religious beliefs help me feel calm when faced with difficult circumstances 10. Difficult circumstances in my life have increased my compassion towards others 7. I feel calm even though I am not in control of my situation
15. My personal religious practice is important to me 11. I want to make the most out of life 8. I accept things I cannot change
16. My participation in religious community is an important aspect of my life 19. Doing something I am passionate about gives me purpose during difficult times 23. I am not getting the support I need
17. I get support from my religious community 20. I find meaning in helping others 24. I am confident that my medical caregivers will respond to my needs
18. My religious beliefs give me hope 26. I seek more of a connection in my relationships 25. My friends provide the support I need during
difficult times
21. Connection with family has become by highest priority 27. I take more time to be in the moment 28. My experience with multiple losses has made it hard to be hopeful during difficult times
22. Support from family lifts my spirits, which gives me hope during difficult times in my life 29. Working through my own grief brings meaning to my life 30. I have a sense of peace in my life
31. I have an increased sense of gratitude 34. Life challenges interfere with activities that are important to me
32. Being surrounded by nature is meaningful
33. Creative arts brings peace to my life
35. Life challenges raised my desire to be positive
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Statistical Analysis

Data are described using frequency (percentage) for categorical data and mean (SD) for continuous data and were assessed for distributional (normality) assumptions. Mixed models for repeated measures were used to analyze NIH-HEALS scores (outcome, dependent variable, continuous data) at each visit over time (week 1, week 3, week 8). These models adjusted for baseline NIH-HEALS score, as is required in repeated measures analysis. In addition, models were adjusted for potential confounding effects of age (continuous) and gender (categorical). Post-hoc comparisons adjusted for multiple comparisons by Dunnet’s method with baseline as the referent comparison. Data were analyzed using SAS v9.4 (SAS Institute, Inc, Cary, NC).

Results

Demographics

Demographic information describing the sample is presented in Table 2. The mean age of participants was 56 years (SD 12). Participants did not identify outside of the gender binary, with 30% identifying as male and 70% as female. The sample was predominantly Caucasian (80%), married (67%), and employed (83%). Most participants (70%) had undergone more than 1 line of cancer therapy. At baseline, participants had a mean HAMD score of 25.4 and mean QIDS score of 12.3, both of which indicate moderate to severe depression. Half of the sample (50%) reported previous antidepressant usage. Patients who had undergone curative treatment for cancer as well as those with advanced metastatic disease were included. Cancer prognosis varied within the sample-nearly half (47%) were diagnosed with curable cancer, while the other half (53%) had non-curable, metastatic cancer.

Table 2.

Demographic and Clinical Characteristics of Study Participants with Cancer

Characteristic Categories % (n=30)
Age, in years: mean (SD) Range 30 – 78 56.1 (12.4)
Gender Female 70.0%
Male 30.0%
Ethnicity/Race African American/Black 10.0%
Asian, Asian American, Pacific 6.7%
Islander 80.0%
Caucasian 3.30%
Hispanic, Latinx
Marital Status Married 66.7%
Divorced/Separated 16.7%
Never Married 16.7%
Employment Status Employed 83.3%
Retired 13.3%
Unemployed 3.33%
Number of Depressive 3 or less 30.0%
Episodes More than 3 40.0%
Unknown 30.0%
Baseline Depression Severity: HAMD 25.4
mean (SD) QIDS-SR 12.3
Prior Antidepressant Use Yes 50.0%
No 36.7%
Unknown 13.3%
Cancer Prognosis Non-curable 53.3%
Curable 46.7%
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Adverse Events (AEs)

The reported adverse events related to psilocybin therapy were generally mild or expected, and included headache (80%), nausea (40%), tearfulness (27%), anxiety (23%), euphoria (23%), fatigue (23%), and mild impairment of psychomotor functioning (10%). These effects resolved at the conclusion of the psilocybin treatment session prior to discharge. There were no notable laboratory changes, ECG abnormalities, or suicidality.

Psycho-Social-Spiritual Wellbeing

NIH-HEALS scores, representing the extent to which one experiences psycho-social-spiritual healing, improved in response to psilocybin treatment (Table 3). All three factors of the NIH-HEALS (Connection, Reflection & Introspection, and Trust & Acceptance), demonstrated positive change. These effects were apparent one day after psilocybin treatment and were sustained up to the last study interval at 8 weeks.

Table 3.

NIH-HEALS Factor and Cumulative Total Scores over Time

Visit n Score Mean (SD) Magnitude of Effect Mean Difference
(95% CI)1 		P-value1
Connection Factor
 Baseline 30 30.8 (9.4)
 Week 1 30 34.3 (9.1) 3.4 (1.3–5.3) 0.002
 Week 3 30 33.8 (89.0) 2.9 (0.7–4.9) 0.012
 Week 8 3 34.7 (9.3) 3.9 (1.4–5.9) 0.003
Reflection & Introspection Factor
 Baseline 30 55.7 (6.8)
 Week 1 30 59.6 (6.8) 3.9 (2.1–6.2) <0.001
 Week 3 30 60.4 (6.4) 4.7 (3.2–7.3) <0.001
 Week 8 30 60.0 (7.9) 4.3 (2.5–7.3) <0.001
Trust & Acceptance Factor
 Baseline 30 32.6 (8.0)
 Week 1 30 39.3 (8.9) 6.7 (3.9–10.3) <0.001
 Week 3 30 39.7 (8.7) 7.1 (4.3–10.9) <0.001
 Week 8 30 39.9 (10.7) 7.3 (4.2–11.7) <0.001
Total Score
 Baseline 30 119.1 (19.4)
 Week 1 30 133.1 (19.9) 14.4 (8.5–20.3) <0.001
 Week 3 30 133.8 (20.3) 15.5 (8.9–20.9) <0.001
 Week 8 30 134.6 (23.7) 16.4 (9.1–23.8) <0.001
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1

From a repeated measures mixed model analyses adjusting for baseline, age, and gender, where follow-up visits were compared to baseline. P-values are corrected for multiple comparisons.

The Connection factor, measuring connection to a higher power and to loved ones, increased by 12.7% on average by week 8 (p = 0.003) the end of the study. Scores on the Reflection & Introspection factor, measuring a sense of meaning, purpose, and gratitude, experience of joy in nature, use of activities that connect mind and body, present moment orientation, and an awareness about the fragility of life, rose by 7.7% by week 8 (p<0.001). Similarly, scores on the Trust & Acceptance factor, measuring the ability to let go of resistance, to feel resolved and at peace with one’s circumstances, and to trust that caregivers, friends, and family will respond to needs as they arise, increased by 22.4% by week 8 (p<0.001). Cumulatively, this totaled to an average of a 16.4-point increase in the NIH-HEALS total scores (p<0.001; Table 3).

Discussion

In this study, cancer patients with depression experienced marked improvements in psycho-social-spiritual wellbeing following psilocybin-assisted therapy, as assessed by the NIH-HEALS. These improvements occurred within the domains of Connection, Reflection & Introspection, and Trust & Acceptance, and were sustained for up to 8 weeks post-dosing. Thus, the results of this study demonstrate that the NIH-HEALS was a useful measure in the context of psychedelic research, and point to a potential mechanism for the psycho-spiritual healing evidenced in cancer patients undergoing psilocybin-assisted therapy.

The results are corroborated by prior psilocybin research, which documented similar changes in cancer patients. Griffiths et al. (2016) utilized the Functional Assessment of Chronic Illness Therapy- Spiritual Well-being (FACIT-sp) to measure changes in the spiritual dimension of quality life across the domains of meaning, peace, and faith, and found improvements up to 6 months post psilocybin treatment. Ross et al. (2016) also found psilocybin therapy to positively influence spiritual well-being in a cancer patient population using FACIT-swb, a modified version with a combined meaning/purpose factor. The NIH-HEALS and its factors are significantly correlated with FACIT-Sp factors (Ameli et al., 2018). Further, the NIH-HEALS offers an assessment of Trust & Acceptance as a component of the healing experience in addition to faith, meaning, and peace.

With a better understanding of the underlying psycho-social spiritual changes, psychedelic-assisted therapies can be tailored to strengthen well-being further during the intervention. Because data suggests that Connection, Reflection & Introspection, and Trust & Acceptance are important elements for psycho-social-spiritual wellbeing, additional focus can be placed on enhancing the development of these factors during therapeutic sessions. For example, therapists leading preparation and integration sessions can emphasize themes of connection, teach mindfulness skills, promote acceptance of life’s circumstances, and encourage awareness of the fragility of life awareness (Rodin et al., 2018). This existential awareness, so called “double awareness” on life and death, vitalizes people to live more fully, while also preparing them for the inevitable transition (Rodin et al., 2018; Holland & Breitbart, 1998).

The renewed interest in psilocybin therapy represents a paradigm shift towards a more holistic approach to treatment. There is an underlying assumption that the psyche holds the tools for its own healing, with psychedelics acting as its catalyst (Grof, 2003; Grinspoon & Doblin, 2008; Mithoefer, 2017). This therapy also addresses the complexity of the whole person, including the mind, body, and spirit (Benor, 2017). While the mind and body have traditionally been regarded as important dimensions, it is noteworthy that the medical field is evolving to incorporate spiritual wellbeing into its definition of health (WHOQOL, 1995). Spirituality was found to be associated with quality of life to the same degree as physical well-being (Brady et al., 1999). Thus, the inclusion of this domain of life in treatment aligns with the current knowledge base on the factors contributing to wellbeing, healing, and quality of life.

Addressing psycho-spirituality might be particularly salient in the cancer patient population, whose diagnoses have radically restructured their lives. In order to experience meaning in life, humans need to comprehend the world around them (coherence), find direction for their actions (purpose), and find worth in their lives (significance) (Park & AI, 2006; Martela & Steger, 2016). Diagnosis of severe and/or life-threatening disease can shatter one’s sense of coherence, basic safety, purpose, and significance (Ameli et al., 2018). However, those who are able to reformulate the world around them and their place within it can emerge on a growth trajectory, with a greater sense of wholeness than before their diagnosis (Tedeschi & Calhoun 1996; Tedeschi et al., 2017; Ameli et al., 2018). Psilocybin is one tool that has the potential to facilitate this transformation in patients by encouraging acceptance of their disease, increasing trust in caregivers, expanding their perspective of self, and deepening a sense of connection to self, others, nature, or a higher power.

The present study was limited by the lack of a control group, a potential for social desirability bias in responding to NIH-HEALS items, and a smaller sample size. In addition, the participants were predominantly Caucasian, female, and employed. These limitations should be considered in terms of the generalizability of the study results. Future studies may aim to reduce these limitations by including a control arm and repeating the treatment in a larger, more diverse sample.

In summary, these findings bring a deeper understanding to the psycho-social-spiritual changes that emerge from psilocybin-assisted therapy, and will hopefully advance the psychedelic field.

Highlights.

  • NIH-HEALS scores, representing psycho-social-spiritual healing, improved in response to psilocybin treatment.

  • All three factors of the NIH-HEALS (connection, reflection & introspection, and trust & acceptance) demonstrated positive change.

  • These effects were apparent at all study time points and were sustained up to the last study interval at 8 weeks

Acknowledgments:

Declared none.

Footnotes

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Conflict of Interest:

The authors confirm that the article content has no conflict of interest

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