Introduction
Cancer distress, characterized as a profound and multifaceted emotional turmoil, can severely impact patients’ ability to cope with their diagnosis and treatment, significantly diminishing their quality of life. The National Comprehensive Cancer Network defines cancer distress as “a multifactorial unpleasant experience of psychological (i.e., cognitive, behavioral, emotional), social, spiritual, and/or physical nature that may interfere with the ability to cope effectively with cancer, its physical symptoms, and its treatment. Distress extends along a continuum, ranging from common normal feelings of vulnerability, sadness, and fears to problems that can become disabling, such as depression, anxiety, panic, social isolation, and existential and spiritual crisis (Smith et al. Reference Smith, Loscalzo and Mayer2018; Vehling and Kissane Reference Vehling and Kissane2018).” Studies have shown that approximately 40–50% of cancer patients experience moderate to clinically significant levels of distress at some point during their illness trajectory (Carlson et al. Reference Carlson, Waller and Mitchell2012; Mehnert et al. Reference Mehnert, Hartung and Friedrich2018). This distress often stems from the emotional burden of a cancer diagnosis itself, treatment side effects, fear of recurrence, previous mental health history financial concerns, lack of social support, and existential concerns (Herschbach et al. Reference Herschbach, Britzelmeir and Dinkel2020; Ikhile et al. Reference Ikhile, Ford and Glass2024; Lewandowska et al. Reference Lewandowska, Rudzki and Lewandowski2020). In advanced cancer stages, existential distress becomes particularly pronounced, manifesting as feelings of hopelessness, meaninglessness, and intense fear of death (Rodin et al. Reference Rodin, Lo and Mikulincer2009). Additionally, cancer distress can profoundly impact both patients and their families’ quality of life, emotional health, roles within the family, and ability to engage in treatment (Caruso et al. Reference Caruso, Nanni and Riba2021; Ferrell and Wittenberg Reference Ferrell and Wittenberg2017; Hodges et al. Reference Hodges, Humphris and Macfarlane2005; Teo et al. Reference Teo, Ng and Bundoc2023). Addressing this distress is crucial for improving the overall well-being and quality of life of patients with cancer, as well as their psychological resilience and ability to cope with the disease (Teo et al. Reference Teo, Krishnan and Lee2019).
Interventions for cancer distress encompass a range of therapeutic approaches (e.g., psychoeducation, cognitive behavior therapy, relaxation training) that target the emotional and physical changes faced by individuals diagnosed with cancer. Research regarding the effectiveness of these interventions demonstrates low to moderate effect sizes (Faller et al. Reference Faller, Schuler and Richard2013; Park et al. Reference Park, Pustejovsky and Trevino2019; Sanijda et al. Reference Sanijda, McPhail and Shaw2018). This highlights the need to explore novel therapeutic interventions that may better address the multifaceted nature of cancer distress.
Psilocybin is a naturally occurring tryptamine found in several mushroom species. It is rapidly hydrolyzed in the liver to the psychoactive compound psilocin. It has been investigated for its potential therapeutic benefits in treating a variety of psychological conditions. Psilocybin acts on serotonin receptors in the brain, particularly the 5-HT2A receptor, which is believed to play a role in mood regulation and cognitive flexibility (Nichols Reference Nichols2016). “Classical psychedelics,” including psilocybin, lysergic acid diethylamide, N,N-dimethyltryptamine, and mescaline, share this mechanism of action but also have complex pharmacologic action at several other receptor sites as well (Kwan et al. Reference Kwan, Olson and Preller2022; Nichols Reference Nichols2016; Reiff et al. Reference Reiff, Richman and Nemeroff2020). Proposed mechanisms for the effects of psilocybin include neurobiological mechanisms, with several potential signaling cascades implicated, which may promote neuroplasticity, as well as psychological mechanisms, including increased cognitive flexibility and the influence of mystical experiences (Doss et al. Reference Doss, Považan and Rosenberg2021; Griffiths et al. Reference Griffiths, Johnson and Carducci2016; Ko et al. Reference Ko, Knight and Rucker2022; Ross et al. Reference Ross, Bossis and Guss2016).
Reported effects of psilocybin include perceptual distortions, labile emotions, euphoria, ego dissolution (a decrease in self-referential thinking), and hallucinations (Kwan et al. Reference Kwan, Olson and Preller2022; Nichols Reference Nichols2016). Classical psychedelics can also cause mystical experiences, which encompass such features as ineffability, transcendence of time and space, universal interconnectedness, and a deeply felt positive mood, among others (Ko et al. Reference Ko, Knight and Rucker2022; Nichols Reference Nichols2016). Such experiences are thought to partially mediate the therapeutic benefits of psychedelics (Reiff et al. Reference Reiff, Richman and Nemeroff2020). In non-cancer patients with depression, psilocybin has shown promise in reducing symptoms of depression and anxiety, contributing to improved emotional and psychological well-being (Carhart-Harris et al. Reference Carhart-Harris, Bolstridge and Rucker2016, Reference Carhart-Harris, Roseman and Bolstridge2018). For patients with cancer who often face the dual challenges of managing a life-threatening illness and coping with the associated psychological burden, psilocybin has been shown to decrease symptoms of depression, anxiety, and existential distress, and increase overall well-being and life satisfaction (Griffiths et al. Reference Griffiths, Johnson and Carducci2016; Ross et al. Reference Ross, Bossis and Guss2016). This therapeutic potential makes psilocybin a promising candidate for addressing the unmet needs of cancer patients, offering a holistic approach that addresses both the emotional and existential dimensions of their distress.
Given the substantial burden of psychological and existential distress in cancer patients and the promising preliminary evidence suggesting the potential efficacy of psilocybin-assisted therapy, there is a clear rationale for conducting a systematic review on this topic. This review will consolidate existing findings, identify consistent outcomes, and highlight areas needing further investigation. This systematic review aims to fill this gap by providing a thorough evaluation of the current evidence, including both quantitative and qualitative data, to better understand the therapeutic potential and safety profile of psilocybin in this context. Additionally, the insights gained from this systematic review will inform and guide the development of our own clinical trial aimed at evaluating psilocybin therapy for distress in cancer patients, with the ultimate goal of improving interventions for managing distress in this population.
Methods
Search strategy and selection criteria
The protocol for this systematic review was registered with the International Prospective Register of Systematic Reviews, PROSPERO (CRD42024511692). The reporting of this systematic review was guided by the standards of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) Statement (Moher et al. Reference Moher, Liberati and Tetzlaff2009).
A comprehensive search of several databases was performed on February 9, 2024 and updated on August 26, 2024. Results were limited to English Language. No date limits for the search were applied. Databases searched (and their content coverage dates) were Ovid MEDLINE(R) (1946+ including epub ahead of print, in-process, and other nonindexed citations), Ovid Embase (1974+), Ovid Cochrane Central Register of Controlled Trials (1991+), Ovid Cochrane Database of Systematic Reviews (2005+), Ovid APA PsycInfo (1967+) and Scopus via Elsevier (1970+).
The search strategies were designed and conducted by a medical librarian with input from the study investigators. Controlled vocabulary supplemented with keywords was used. The strategies listing all search terms used and how they were combined are available in the supplemental material.
Data extraction and quality assessment
Randomized controlled trials (RCTs), open-label or case series studies, and single case reports that met the inclusion criteria were selected. Extracted study information included study characteristics (authors, year of publication, location), participant demographics (age, gender, diagnosis), details of psilocybin (formulation, dose, frequency, duration, other treatment parameters) and psychotherapy interventions, study methodology (study design, randomization, control condition, blinding), outcome measures (primary and secondary outcomes, tools or instruments used), and results (distress and other psychological measures/scores before and after intervention, effect sizes, statistical significance). Covidence software was utilized for review, data extraction, and reporting. Two authors independently screened titles and abstracts, selected articles for full-text review, and extracted data. Two reviewers independently assessed the quality of RCTs using the Cochrane Risk of Bias Tool (Schunemann et al. Reference Schunemann, Higgins and Thomas2019) and evaluated non-randomized studies using the Methodological Index for Non-Randomized Studies (MINORS) criteria (Slim et al. Reference Slim, Nini and Forestier2003). Any disagreements were resolved through discussion until a consensus was reached.
Results
Search results
A total of 576 abstracts and titles were initially identified from database searches. After removing duplicates and irrelevant studies, 42 studies were assessed for eligibility, out of which 28 studies were excluded. Fourteen studies met the inclusion criteria and were included in the systematic review, as shown in the PRISMA flow diagram (Fig. 1).
PRISMA flow diagram.
Characteristics of included studies
RCTs
Three RCTs collectively demonstrated the efficacy and safety of psilocybin in reducing anxiety and depression in patients with life-threatening cancer (Table 1). Griffiths et al. (Reference Griffiths, Johnson and Carducci2016) conducted a double-blind cross-over trial with 51 patients, revealing that a high dose of psilocybin led to substantial and sustained decreases in depression and anxiety, with effects lasting up to six months. Grob et al. (Reference Grob, Danforth and Chopra2011) conducted a pilot within-subject study with 12 patients, reporting significant reductions in anxiety and mood improvements following psilocybin treatment that lasted for several months. Ross et al. (Reference Ross, Bossis and Guss2016) found that a single dose of psilocybin significantly reduced anxiety and depression symptoms in 29 patients, with improvements persisting for six months and notable enhancements in quality of life and emotional well-being. Adverse effects across these studies were generally mild and transient, including blood pressure elevations, headaches, nausea, and temporary anxiety, with no serious adverse events reported.
Summary of included studies
5D-ASC – 5-Dimension Altered States of Consciousness; ASD – Acute Stress Disorder; AUDIT – Alcohol use Disorder Identification Test; BDI – Beck Depression Inventory; BP – Blood pressure; BPRS – Brief Psychiatric Rating Scale; BSI – Brief Symptom Inventory; CESD-R – Center for Epidemiological Studies Depression Scale-Revised; CGI-S – Clinical Global Impressions Scale, severity of illness; C-SSRS – Columbia Suicidality Severity Rating Scale; DS-II – Demoralization Scale II; DSM – Diagnostic and Statistical Manual of Mental Disorders; DUDIT – Drug Use Disorders Identification Test; EQ-5D-5 L – EuroQOL-5-dimension-5-level scale; FACIT-Sp – Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale, version 4; GAD – Generalized Anxiety Disorder; GAD-7 – Generalized Anxiety Disorder-7 item; GRID-HAMD-17 – GRID-Hamilton Rating Scale for Depression; HADS – Hospital Anxiety and Depression Scale; HADS A – Hospital Anxiety and Depression Scale Anxiety; HADS D – Hospital Anxiety and Depression Scale Depression; HADS T – Hospital Anxiety and Depression Scale Total; HAM-A with SIGH-A – Hamilton Anxiety Rating Scale assessed with Structured Interview Guide for the Hamilton Anxiety Scale; HR – Heart rate; LAP-R – Life Attitude Profile – Revised; MADRS – Montgomery-Asberg Depression Scale; Maudsley – Maudsley Visual Analog Scale; MDD – Major depressive disorder; MEQ-30 – Death Transcendence Scale – Mystical Experience Questionnaire; MoCA – Montreal Cognitive Assessment; MQOL – McGill Quality of Life; Pain VAS – Visual Analog Scale; PHQ-9 – Patient Health Questionnaire-9 item; POMS – Profile of Mood States; PTSD – Posttraumatic stress disorder; QIDS-SR – Quick Inventory of Depressive Symptomatology-Self Report; QUICK – Quick Inventory of Depressive Symptomatology-Self Report; RCT – Randomized controlled trial; SAE – Serious adverse events; SAHD – Schedule of Attitudes towards Hastened Death; SD – Standard deviation; SDS – Sheehan Disability Scale; STAI – State-Trait Anxiety Inventory; STAI-S – State-Trait Anxiety Inventory State Anxiety; STAI-T – State-Trait Anxiety Inventory Trait Anxiety; SEM – Standard Error of the Mean; Temp – Temperature.
Open-label studies
Five open-label trials investigated psilocybin-assisted therapy for cancer-related distress, showing promising outcomes in psychological, social, and spiritual well-being (Table 1). In a long-term follow-up study from an RCT conducted by Ross et al. (Reference Ross, Bossis and Guss2016), Agin-Liebes and their team found sustained improvements in psychiatric and existential distress up to 4.5 years post-psilocybin treatment (Agin-Liebes et al. Reference Agin-Liebes, Malone and Yalch2020). Agrawal et al. (Reference Agrawal, Richards and Beaussant2023) conducted psilocybin-assisted group therapy in cancer patients with major depressive disorder, noting significant reductions in depression and anxiety and enhanced group cohesion. Anderson et al. (Reference Anderson, Danforth and Daroff2020) studied psilocybin-assisted group therapy in demoralized older men who are long-term AIDS survivors and cancer survivors, reporting improved mood and emotional well-being. Reported adverse events during dosing included hypertension, nausea, anxiety, paranoia, hallucinations, and transient thought disorder. Lewis et al. (Reference Lewis, Byrne and Hendrick2023) conducted the Hopkins-Oxford Psychedelics Ethics (HOPE; A Pilot Study of Psilocybin Enhanced Group Psychotherapy in Patients with Cancer) pilot study, focusing on psilocybin-enhanced group psychotherapy for cancer patients, which resulted in significant distress alleviation and enhanced group support, with adverse effects such as hypertension, nausea, and headache requiring medications. Shnayder et al. (Reference Shnayder, Ameli and Sinaii2023) found that psilocybin-assisted therapy significantly improved psycho-social-spiritual well-being in cancer patients, highlighting its potential as a holistic therapeutic approach.
Single case report
Patchett-Marble et al. (Reference Patchett-Marble, O’Sullivan and Tadwalkar2022) presented a case report detailing the use of psilocybin mushrooms to treat psychological and existential distress in a patient with lung cancer. The patient experienced significant relief from anxiety, depression, and existential distress after a single session, with improvements in quality of life and emotional well-being sustained at 4 months.
Qualitative studies
Five qualitative studies provide insights into patients’ experiences undergoing psilocybin-assisted therapy for cancer-related distress, complementing the quantitative results from RCTs and open-label trials. (Table 2) Beaussant et al. (Reference Beaussant, Tarbi and Nigam2023) reported high acceptability and significant emotional and psychological benefits from psilocybin-assisted group therapy in patients with cancer and major depressive disorder. Belser et al. (Reference Belser, Agin-Liebes and Swift2017), Swift et al. (Reference Swift, Belser and Agin-Liebes2017), and Malone et al. (Reference Malone, Mennenga and Guss2018) derived their data from the previously cited Ross RCT. Belser et al. (Reference Belser, Agin-Liebes and Swift2017) reported emotional and spiritual experiences that led to lasting reductions in existential distress and enhanced well-being. Swift et al. (Reference Swift, Belser and Agin-Liebes2017) highlighted transformative emotional and existential experiences, providing insights into long-term psychological benefits. Malone et al. (Reference Malone, Mennenga and Guss2018) described the individual experiences of four cancer patients, reporting profound personal insights, emotional breakthroughs, and a renewed sense of meaning. Lewis et al. (Reference Lewis, Byrne and Hendrick2023) provided observations from the HOPE trial, focusing on group-format psychedelic-assisted therapy. Patients emphasized the therapeutic value of shared experiences and group support, contributing to significant emotional relief and enhanced social connectedness.
Summary of qualitative studies
ASD – Acute stress disorder; DSM – Diagnostic and Statistical Manual of Mental Disorders; GAD – Generalized Anxiety Disorder; MDD – Major depressive disorder; HOPE – A Pilot Study of Psilocybin Enhanced Group Psychotherapy in Patients with Cancer.
Psychotherapy interventions
The psychotherapy interventions across the reviewed studies varied in conceptual basis and structure, incorporating individual and group therapy formats (Table 3). Grob et al. (Reference Grob, Danforth and Chopra2011) utilized supportive therapy principles, focusing on individual preparation and emotional support during dosing, with limited details on the integration phase. The Griffiths et al. (Reference Griffiths, Johnson and Carducci2016) and Ross et al. (Reference Ross, Bossis and Guss2016) studies combined supportive-expressive and existential psychotherapy approaches, emphasizing individual preparation and integration through several hours of meetings to discuss meaningful life aspects and process the psilocybin experience. In contrast, Agrawal et al. (Reference Agrawal, Richards and Beaussant2023) adapted the COMPASS Pathways model for a group format, integrating psychoeducation and supportive techniques with both group and individual sessions for preparation and integration. Anderson et al. (Reference Anderson, Danforth and Daroff2020) employed a model based on Brief Supportive Expressive Group Therapy (SEGT), emphasizing emotional expression and support, with a mix of individual and group sessions to prepare for and integrate the psilocybin experience. Lewis et al. (Reference Lewis, Byrne and Hendrick2023) and Shnayder et al. (Reference Shnayder, Ameli and Sinaii2023) incorporated SEGT principles combined with psychoeducation, focusing on trust-building, coping strategies, and processing experiences through group and individual sessions.
Summary of psychotherapy interventions
NA = Not applicable.
Risk of bias assessment
The qualitative assessment of the included RCT studies, evaluated using the Cochrane Risk of Bias Tool, and the open-label studies, assessed with the MINORS criteria, are presented graphically and in tabular form in the supplemental material. Overall, the quality of the studies was found to be modest. In RCTs, blinding of the psilocybin arm would be very difficult, as expected.
Discussion
The findings from this systematic review highlight the potential of psilocybin as a therapeutic intervention for depression, anxiety, and overall mood improvement in patients with cancer. This therapy may help reduce depression and anxiety while improving overall quality of life and emotional well-being. These benefits have been observed across RCTs and open-label trials, indicating a therapeutic potential that warrants cautious further exploration.
Ethical considerations
The consensus from the HOPE Working Group emphasized the need to consider all the ethical dimensions of psilocybin-assisted therapy (Jacobs et al. Reference Jacobs, Earp and Appelbaum2024). The HOPE workshop discussed the contributions and rights of Indigenous communities with long histories of using psychedelic substances and the need to engage with these communities respectfully and equitably for ethical research and clinical practices. The workshop also highlighted the need for a precautionary approach to advancing scientific understanding. Despite promising safety profiles, the long-term and contextual risks of psilocybin are not fully understood, necessitating comprehensive and representative research efforts. This aligns with our systematic review findings that while psilocybin therapy shows potential benefits, more diverse and extensive studies are needed to generalize results across different populations and settings.
Addressing safety concerns and ensuring appropriate use
While the potential benefits of psilocybin-assisted therapy are encouraging, it is crucial to acknowledge concerns related to the use of psychedelics, particularly in the context of rising recreational use. Psychedelics, including psilocybin, are not without risks, and their misuse and abuse can lead to adverse outcomes. However, the studies included in our systematic review involved psilocybin administered in structured clinical settings with comprehensive support from trained therapists. This controlled environment is essential for ensuring safety and maximizing therapeutic benefits. Appropriate use and rigorous monitoring are key to mitigating risks. This includes thorough patient screening, careful dosing, close supervision during and after the psychedelic experience, and extensive training for therapists. These measures help prevent potential misuse and ensure that therapy is safe and effective (Schlag et al. Reference Schlag, Aday and Salam2022). Patients with a history of, or strong family history of, psychosis or bipolar disorder should be excluded from these treatments (Johnson et al. Reference Johnson, Richards and Griffiths2008).
Despite the promise of psychedelic-assisted therapies, there is a critical need for improved risk-benefit assessments and broader, more inclusive studies to safely integrate these therapies into modern healthcare (Bradberry et al. Reference Bradberry, Gukasyan and Raison2022). Addressing potential psychiatric risks, such as transient effects and worsening mood or psychosis in susceptible individuals, is essential. These challenging experiences, however, may lead to improved outcomes (Griffiths et al. Reference Griffiths, Johnson and Carducci2016). Integrating psychedelic therapy education into psychiatric and clinical psychology training programs may also help address potential access bottlenecks as well as ensure providers are trained in comprehensive risk-benefit evaluations for patients. Providing strong patient support and establishing appropriate regulatory frameworks will be essential for safely and effectively implementing these therapies (Bradberry et al. Reference Bradberry, Gukasyan and Raison2022).
Importance of psychotherapy in psilocybin treatment
A critical aspect of the efficacy of psilocybin in these studies is its use in conjunction with psychotherapy. The therapeutic setting, including preparation, dosing, and integration sessions, is vital in maximizing benefits and mitigating risks. Psilocybin-assisted psychotherapy provides a structured environment where patients can safely and meaningfully process their experiences. The supportive presence of trained therapists helps guide patients through challenging emotions, facilitating deeper insights and emotional breakthroughs. The combination of psilocybin with psychotherapy is crucial for achieving therapeutic outcomes, ensuring the psychedelic experience is integrated into the patient’s broader psychological context.
The studies in our systematic review demonstrate the flexibility of psilocybin-assisted psychotherapy, utilizing individual and group therapy formats to provide comprehensive support throughout the therapeutic process. The choice between individual and group therapy formats reflects different therapeutic goals and logistical considerations, with group therapy offering opportunities for shared experiences and mutual support. In contrast, individual therapy provides tailored, one-on-one attention to address personal concerns. Incorporating spiritual, existential, and psychological components, psilocybin-assisted psychotherapy shows promise in significantly reducing psychological distress in patients with cancer. Still, it requires careful monitoring and culturally sensitive care to maximize benefits and mitigate risks (Palitsky et al. Reference Palitsky, Kaplan and Peacock2023).
Meaningfulness of small improvements in distress
In the context of life-threatening illnesses such as cancer, even small improvements in psychological and existential distress can be profoundly meaningful. Patients with terminal diagnoses often experience high levels of anxiety, depression, and existential dread, which can severely impact their quality of life (Krikorian et al. Reference Krikorian, Limonero and Maté2012). The ability to alleviate these symptoms through psilocybin-assisted therapy, even modestly, can significantly enhance a patient’s emotional and psychological well-being. For many patients with cancer, a reduction in distress can translate into an improved ability to enjoy meaningful interactions with loved ones, better engagement in daily activities, and a greater sense of peace as they navigate their illness.
Limitations and areas for future research
While the current body of evidence is promising, it has limitations. The relatively small sample sizes, modest study quality, and the open-label design of several studies introduce potential biases. In RCTs, patients can often tell whether they have received psilocybin or a placebo due to the noticeable effects of the psychedelic, which can affect the study blinding and outcomes. Future research should focus on larger, multi-center RCTs to confirm these findings and further explore the combined therapeutic effects of psilocybin and the associated therapy. Additionally, investigating the long-term impact of psilocybin-assisted therapy on different cancer types and stages will provide a more comprehensive understanding of its applicability. Expanding research to include diverse populations and settings will help generalize the findings. There is also potential in exploring synthesized molecules that do not have the psychedelic effect, as suggested by Dr. Charles Raison, a prominent researcher in the field of psychedelic studies.
Clinical implications
Psilocybin-assisted therapy has shown the potential to offer a rapid and sustained reduction in symptoms of depression and anxiety among cancer patients, which is particularly relevant in palliative care settings. The reported long-term benefits suggest that a limited number of psilocybin sessions could lead to enduring improvements in distress. However, these findings are preliminary and should be interpreted with caution until validated by larger, more rigorous studies.
Conclusion
This systematic review is unique in that it comprehensively examines the effects of psilocybin on cancer-related distress, highlighting its potential as a therapeutic option. Psilocybin-assisted therapy may help alleviate psychological and existential distress in cancer patients, with benefits observed across multiple studies. While these findings are encouraging, they should be approached with cautious optimism. More large-scale, well-designed RCTs are needed to confirm these results and address existing research gaps. Integrating psilocybin-assisted therapy into clinical practice under appropriate supervision and with rigorous monitoring could offer a viable treatment option for managing distress in cancer patients. Additionally, the findings from this systematic review will inform and guide the development of our own clinical trial to evaluate psilocybin therapy for distress in cancer patients, aiming to improve interventions for managing distress in this population.
Funding
Funding for statistical support from the Mayo Clinic Department of Medical Oncology.
Competing interests
Maria I. Lapid, Kenneth R. Olivier, and Stacy D. D’Andre, via Mayo Clinic Ventures, have a relationship with PurMinds Neuropharma related to the development of psychedelic therapies for cancer patients, with the potential for future royalties. This relationship did not influence the design, conduct, or findings of this systematic review.
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