The effects of psilocybin on psychological distress in cancer patients: a systematic review and meta-analysis

Abstract

Introduction

Psilocybin may effectively treat psychological distress in cancer patients. A meta-analysis assessed its safety and effectiveness in this context.

Methods

A comprehensive search across six databases (Scopus, PsycINFO, PubMed, Cochrane, CINAHL Complete, and Web of Science) was conducted to identify studies on psilocybin’s effects on mental health in cancer patients up to November 2024. Both randomized and non-randomized trials were included, assessing anxiety, depression, and other mental outcomes at short-term (2–5 weeks) and long-term (6 months) follow-ups. Study quality was assessed using Cochrane tools, and statistical analyses were performed with Stata version 17.

Results

In randomized controlled trials (RCTs), psilocybin significantly reduced depressive symptoms, with the Beck Depression Inventory (BDI) (standardized mean difference [SMD] = − 2.87, 95% confidence interval [CI]: − 3.99 to − 1.76, p < 0.001) and the Hospital Anxiety and Depression Scale–Depression subscale (HADS-D) (SMD = − 2.97, 95% CI: − 3.60 to − 2.33, p < 0.001) showing strong effects. Anxiety outcomes were mixed: the Hospital Anxiety and Depression Scale–Anxiety subscale (HADS-A) was not significant (SMD = − 3.63, p = 0.11), while the State-Trait Anxiety Inventory (STAI) also showed inconsistent results. Short-term analyses (2–5 weeks) revealed significant improvements in the BDI (SMD = − 1.17), HADS-D (SMD = − 1.58), and HADS-A (SMD = − 1.99), all p < 0.001. Long-term analyses (6 months) demonstrated sustained benefits on the BDI (SMD = − 2.60, p = 0.04) and HADS-D (SMD = − 3.56, p = 0.01). Measures of quality of life (QOL) and spiritual well-being using the Functional Assessment of Chronic Illness Therapy–Spiritual Well-Being (FACIT-Sp) scale also improved significantly after psilocybin treatment.

Conclusion

Psilocybin may reduce depressive symptoms in cancer patients, with mixed effects on anxiety and time-dependent improvements in spiritual well-being and (in single-arm data) quality of life. Given the small number of studies, high heterogeneity, challenges with blinding/expectancy, and frequent co-intervention with psychotherapy, these findings are preliminary. Larger, rigorously blinded trials are needed to determine clinical effectiveness and safety.

Supplementary Information

The online version contains supplementary material available at 10.1186/s40359-025-03935-y.

Introduction

Psychedelics are a class of substances primarily recognized for their effects on cognition and perception, often causing altered states of consciousness through diverse mechanisms of action [1]. Classic serotonergic psychedelics, such as psilocybin, exert their effects mainly by activating 5-hydroxytryptamine (5-HT) receptors. Psilocybin (4-phosphoryloxy-N, N-dimethyltryptamine), commonly known as “magic mushrooms,” is a natural tryptamine/indoleamine compound with a long history of traditional use and a favorable safety profile [1–3]. It was first synthesized and purified by Swiss chemist Albert Hofmann in the late 1950s [1]. In 1968, however, psilocybin was prohibited worldwide due to concerns over recreational misuse, halting scientific research for decades [4]. In the past decade, interest has re-emerged, with research centers once again exploring its therapeutic potential [1, 5].

Psilocybin is rapidly hydrolyzed in the body to its active lipophilic metabolite, psilocin (4-hydroxy-N, N-dimethyltryptamine), which has a half-life of about 50 min and reaches peak plasma concentrations 80–100 min after ingestion [6, 7]. Psilocin readily crosses the blood–brain barrier and primarily agonizes serotonin (5-HT) receptors—particularly 5-HT2A, but also 5-HT2C, 5-HT1A, and 5-HT1B. These receptors are abundantly expressed in cortical regions (prefrontal, frontal, temporal, and occipital lobes) as well as in the basal ganglia, where their activation increases glutamate release, leading to hallucinogenic effects, psychotic-like symptoms, and heightened cortical activity [2]. Although psilocybin and psilocin lack affinity for dopamine D2 receptors, evidence suggests an indirect activation of dopaminergic systems without addictive potential. Given the association between low mesolimbic dopamine levels and depression, psilocybin may exert part of its antidepressant effect by enhancing dopaminergic activity and compensating for dopamine deficiency [1]. Human clinical studies have demonstrated therapeutic benefits of psilocybin in conditions such as major depressive disorder (MDD) [8], smoking cessation [9, 10], alcohol use disorder [11], as well as anxiety and depression [12, 13]. While psilocybin generally shows a favorable safety profile and low toxicity, acute effects such as anxiety, nervousness, delusions, tachycardia, hypertension, kidney injury, and gastrointestinal symptoms (e.g., nausea and vomiting) have been reported, though usually mild and transient. Rare but serious outcomes—including psychosis, suicide during psychotic episodes, and death—have been described, underscoring the importance of safety guidelines and clinical supervision [6, 7, 14].

Psychological distress is a frequent condition among patients following a cancer diagnosis [15]. It encompasses depression, anxiety, and a diminished sense of spirituality [16]. Elevated levels of depression and anxiety in this context are associated with worse cancer prognosis, partly through increased inflammatory and tumor-promoting markers, impaired immune responses, and reduced DNA repair capacity at the cellular level [17]. Loss of spirituality is another important dimension of psychological distress, defined as a disruption in one’s sense of life purpose, connection to others, and relationship with a higher power [18]. Cancer can profoundly challenge these perceptions, leading to distress. Evidence suggests that strengthening spirituality in patients with cancer alleviates psychological distress by fostering meaning, acceptance of illness, and emotional calm [19, 20]. Furthermore, lower levels of spirituality after diagnosis negatively influence life appreciation and decision-making, including choices regarding life-sustaining treatments that may extend survival [21].

Overall, psychological distress in cancer patients is linked to higher mortality, reduced survival, poorer treatment adherence, diminished quality of life, prolonged hospitalization, unfavorable medical outcomes, and an increased risk of suicide [22–24]. Despite these consequences, psychological distress often remains underrecognized and inadequately addressed throughout the disease course [17]. These findings highlight the critical importance of early identification and timely intervention for mental health conditions in oncology care.

Currently, psychotherapy and conventional pharmacotherapy—primarily tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs)—are the main treatments for psychological distress in cancer patients [25, 26]. However, their efficacy, safety, and patient compliance remain debated [4, 25]. Psychotherapy often provides only short-term benefits, and studies suggest that both psychotherapy and standard antidepressants have limited impact on psychological distress in patients with life-threatening cancers [4, 23, 25]. Additional concerns include delayed therapeutic onset [22, 25], drug tolerance, interactions with chemotherapy [25], low response rates, adverse events leading to discontinuation, and frequent relapse [23, 27]. These limitations underscore the urgent need for more effective and innovative treatments [27]. Psilocybin, with its sustained effects on psychological and existential distress and a generally favorable safety profile, emerges as a promising therapeutic option in this context [15, 22, 23, 27–29].

The evidence around routine clinical use of psilocybin in managing psychological distress has been inconclusive. While recent reviews report psilocybin as an efficient and revolutionary treatment that is superior to classic antidepressants [1, 5, 12, 30–33], antidepressants are still the primary choice of treatment, and psilocybin therapy is considered to be more of an experimental therapy due to inadequate supporting evidence [34, 35]. Recently, two reviews have attempted to provide more confident results on this topic [36, 37].

In a systematic review in 2024, Bader et al., included 7 studies including clinical trials and observational studies (132 participants in total) to investigate the efficacy of psilocybin in managing psychological symptoms in patients with advanced stages of cancer. They have shown that psilocybin can significantly improve the anxiety symptoms along with the quality of life and pain control in these patients. The quantitative analysis of the study has also proved significant anxiety relief in participants [37]. We believe that the current systematic review and meta-analysis will be a complementary evidence to the mentioned study since we’ll focus not only on anxiety dimension of the psychological distress, but also assess how psilocybin may affect depression and spirituality of the patients, considering them as important as anxiety in perceived levels of distress.

Also a recent Cochrane systematic review and meta-analysis of randomised controlled trials(RCTs), has been conducted and assessed how effectively psychedelics(including psilocybin, LSD and MDMA) may improve anxiety, depression and existential distress in patients with life-thretening disorder diagnosis including cancer. The analysis has shown improvement in anxiety and depression states along with spirituality and quality of life after receiving classic psychedelics, although the robustness and generalizablitiy of the results were limited due to small sample size [36]. To have a better understanding of the specific role of psilocybin, as an emergent member of psychedelics, in improving psychological distress, the present study will only focus on clinical trials which administered psilocybin as the main treatment in their study designs and will include randomised, non-randomised and single arm studies to provide a systematic review and meta-analysis of the previous clinical trials.

Methods

A systematic review and meta-analysis evaluated psilocybin’s effects on cancer patients, registered under CRD42023460787, following PRISMA guidelines [38].

Search strategy

The search strategy comprised two main components: database searches and grey literature. Key terms such as “psilocybin” and “cancer,” along with relevant synonyms and MeSH terms, were used. Databases including Scopus, PsycINFO, PubMed, CINAHL Complete, and Cochrane were searched for English-language publications up to November 2024, without restrictions. Detailed strategies for each database are provided in the Supplementary Material. Additionally, citation lists of included studies and clinical trial registries were screened to identify further relevant articles.

Eligibility criteria

We performed a review of interventional studies examining psilocybin’s effects on cancer patients aged 18 and older. To define the PICOS criteria for the study the components as follows:

• Population (P): Adults aged 18 and older diagnosed with cancer.

• Intervention (I): Administration of psilocybin or psilocybin-containing substances.

• Comparison (C): Comparisons included placebo or standard care groups. However, we also, included single-arm designs (without control group) focusing solely on psilocybin.

• Outcomes (O): Reporting results concerning psychological well-being, depression, anxiety, spiritual well-being, and quality of life as evaluated using validated assessment tools.

• Study Design (S): This encompassed RCTs and quasi-experimental studies, as well as long-term follow-ups of previously conducted studies published in English-language peer-reviewed journals.

Our exclusion criteria encompassed studies unrelated to cancer, those with insufficient or unavailable data (e.g., findings reported without access to original datasets, preventing meta-analysis but permitting inclusion in the systematic review), duplicate publications, and non-interventional designs. Two investigators (SM and AG) independently screened studies for eligibility. Discrepancies were resolved through discussion and, when necessary, consultation with a third investigator (RM).

Study selection

Two authors (SM and AG) conducted the initial screening of potentially eligible studies by reviewing titles and abstracts in EndNote (version 20), applying predefined inclusion and exclusion criteria to identify studies requiring full-text assessment. The full texts of selected articles were then independently retrieved and evaluated by the same authors. Disagreements regarding study design, methodology, or eligibility were resolved in consultation with two additional reviewers (RM and MP). The number of studies included and excluded at each stage was documented and presented in a PRISMA flowchart.

Data extraction

Two authors, SM and AG, independently collected data from the included articles. Any disagreements that arose were resolved through discussions involving a third author, RM. The information extracted from each study encompassed various general attributes, including the primary author, publication year, study setting, research design, participant details, interventions, findings, adverse events, and limitations.

Risk of bias assessment

The risk of bias and quality of the included studies were assessed using Cochrane tools [39] based on the design of the included studies. The Risk of Bias-2 (ROB-2) tool, also known as the Cochrane Risk of Bias Tool for Randomized Trials [40], was used for evaluating bias. This tool is structured into five domains (D) to assess potential bias. The study quality was assessed and categorized into three levels: high risk of bias, few concerns, and low risk of bias. For non-randomized studies, the Risk of Bias In Non-randomized Studies - of Interventions-1 (ROBINS-1) tool [41] was used. The ROBINS-1 tool assesses study quality based on domains such as bias due to confounding, selection of participants, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes, and selection of the reported result. The total score on the scale corresponds to one of four quality ratings: low, moderate, serious, or critical risk of bias. The risk of bias in the secondary analysis was regarded as equivalent to that in their previously published study.

Quantitative analysis

To prepare the data for analysis, two approaches were used. The placebo-controlled analysis compared changes in outcomes between before and after treatment in both the psilocybin and control groups two weeks post-intervention. In contrast, the single-arm analysis focused solely on the psilocybin group, examining mean differences in targeted variables before and after treatment over both short-term (2–5 weeks) and long-term (6 months) periods.

The standardized mean difference (SMD) was calculated to assess the overall effect size based on mean changes and standard deviations (SD) of outcomes such as depression, anxiety, and spiritual well-being from both psilocybin and control groups in RCTs. The SD was computed using the standard error (SE) alongside a 95% confidence interval (CI), following Hozo et al.’s methodology [42]. Heterogeneity is evaluated using the I² test, where the degree of heterogeneity varies from low (0–40% I²) to high (75–100% I²). A random effects model combined SMD and confidence intervals across studies, while heterogeneity was evaluated using the chi-squared test and I² statistic. Publication bias was assessed using Egger’s regression test and visual inspection of funnel plots, performed only when at least three effect sizes were available. All statistical analyses conducted using Stata-17 software, where significance was set at P-values below 0.05.

Results

Selection of studies

The PRISMA flow diagram in Fig. 1 illustrates the article selection process. Initially, 1,176 articles were identified through specific keywords. After removing 410 duplicates with EndNote and excluding 714 based on title and abstract screening, 52 articles were left. Full-text evaluation led to the exclusion of 44 articles, resulting in eight studies [15, 22, 23, 28, 43–46] being included in the final analysis. Three of these studies [15, 43, 46] that two of them were based on secondary data (long term follow up) from a previous study [22] and another one was the secondary analysis of published study [45]. However, since their data had not been previously documented in the earlier report, they were ultimately included in the final comprehensive study. Additionally, one study [47] was excluded because it lacked quantitative data and new information.

Fig. 1.

PRISMA flowchart of the included studies

Study characteristics

A total of seven studies [15, 22, 23, 28, 43–45] were included in this review, published between 2011 and 2023, with sample sizes ranging from 11 to 51. The study population consisted of patients above the age of 18 and had a psychiatric disorder based on DSM-IV or DSM-V criteria. All seven studies were conducted in the United States. Three studies [22, 23, 28] were designed as double-blind, controlled crossover trials. Two studies [44, 45] followed a non-randomized design. Two additional studies [15, 43] conducted long-term follow-up assessments of previously conducted studies, providing novel data. One study by Ross et al. in 2021 [43] and another by Agin-Liebes et al. in 2020 [15] included individuals who had previously participated in the 2016 trial conducted by Ross [22]. The study by Malone et al. was excluded due to its qualitative design [47].

The administration of psilocybin varied across the included studies. Ross et al. [22] and the two long-term follow-up studies used a dosage of 0.3 mg/kg. Griffiths et al. [23] estimated the dosage to be between 0.31 and 0.43 mg/kg. Lewis et al. [44] and Shnayder et al. [45] utilized a fixed dosage of 25 mg. Grob et al. [28] employed a lower dosage of 0.2 mg/kg. Except for Grob et al. [28], all studies also incorporated psychotherapy sessions alongside the administration of psilocybin.

Different questionnaires were utilized to assess the effects of psilocybin, and a subset of them is mentioned here. Ross et al. [22] employed the HADS (Hospital Anxiety and Depression Scale), BDI (Beck Depression Inventory), STAI (State-Trait Anxiety Inventory), and FACIT-Sp (Functional Assessment of Chronic Illness Therapy - Spiritual Well-being) questionnaires. In their subsequent study in 2021, Ross et al. [43] used used the DS (Demoralization Scale), BDI, and BSI (Brief Symptom Inventory). Lewis et al. [44] utilized the HAM-D (Hamilton Depression Rating Scale) and FACIT-Sp questionnaires. Agin-Liebes et al. [15] used the HADS, BDI, STAI, and FACIT-Sp questionnaires. Grob et al. [28] employed the STAI, BDI, and POMS (Profile of Mood States). Griffiths et al. [23] used the GRID-HAMD (GRID Hamilton Rating Scale for Depression), HAM-A (Hamilton Anxiety Rating Scale), BDI, HADS, STAI, and POMS. Shnayder et al. [45] utilized the NIH-HEALS (National Institutes of Health Healing Experience of All Life Stressors) questionnaire.

In the various studies, the effects of psilocybin were assessed both in the short-term and long-term. Significant differences in depression were observed between the groups that received psilocybin and the control groups. These significant differences were seen in studies conducted by Ross et al. [22] at 1 day, 2 weeks, 6 weeks, and 7 weeks; Grob et al. [28] at 6 months; Agin-Liebes et al. [15] at 3.2 and 4.5 years; and Griffiths et al. [23] t 5 weeks. Lewis et al. [44] also reported significant reductions in depression at 2 weeks and 26 weeks after treatment. Regarding anxiety, similar significant differences were found in the studies conducted by Ross et al. [22], Grob et al. et al. [28], Agin-Liebes et al. [15], and Griffiths et al. [23] at various short-term and long-term time points. In terms of spirituality, improvements were observed in the study by Ross et al. [22] at 2 weeks and 6.5 months after sessions, Agin-Liebes et al. [15] at the 4.5-year follow-up, and Shnayder et al. [45] at 1 day, 1 week, 3 weeks, and 8 weeks. In a long-term follow-up study in 2021, Ross et al. [43] observed significant reductions in suicidal ideation after a 6-month follow-up, along with a persistent decrease in loss of meaning lasting for 4.5 years when compared to the baseline. Table 1 provides a summary of the characteristics of the trials included in the study.

Table 1.

Characteristics of included studies

Author	Setting	Design	ClinicalTrials.gov Identifier	Participants	Intervention	Control	Finding	Side effect	Limitations
Ross et al., 2016 [22]	US	Randomized controlled trial	NCT00957359	N = 29 (18 women), mean age 56.28 years (SD = 12.93) with cancer meeting DSM-IV criteria for an adjustment disorder or generalized anxiety disorder	Psilocybin (0.3 mg/kg) + psychotherapy	Niacin (250 mg) + psychotherapy	Significant differences were found between the psilocybin-first and placebo-first groups in psychological measures, which include HADS Total, HADS Anxiety, HADS Depression, BDI, STAI-State, STAI-Trait, and spirituality. The differences were observed at 1 day, 2 weeks, 6 weeks, and 7 weeks after the first session, and 1 day and 6 weeks after the second session. Improvements in HADS Total, HADS Depression, STAI-Trait, and spirituality were sustained for 6.5 months.	- No serious adverse events - Side effects: elevations in blood pressure and heart rate, headache, nausea, anxiety, psychotic-like symptoms, paranoid ideation, thought disorder	- The effects of psilocybin and the psychotherapeutic session cannot be differentiated. - Limited diversity (90% Caucasian) - Self-report outcomes - Small sample size
Ross et al., 2021 [43] [22]	US	Long-term follow-up after RCT	NCT00957359	N = 11 (7 women), mean age 60.3 years (SD = 7.1) with cancer meeting DSM-IV criteria for adjustment disorder with anxiety ± depression, acute stress disorder, generalized anxiety disorder, or anxiety disorder	Psilocybin (0.3 mg/kg) + psychotherapy	No	Significant differences were found between the psilocybin-first and placebo-first groups in terms of loss of meaning at 2 weeks after the first session. There were no differences between the groups regarding suicidal ideation. Suicidal ideation and loss of meaning showed reductions from baseline, with reductions in suicidal ideation apparent 8 h after treatment and lasting for 6.5 months, and reductions in loss of meaning apparent 2 weeks and lasting for 4.5 years.	NR	- A crossover design without a true control group cannot effectively assess long-term effects. - The effects of psilocybin and the psychotherapeutic session cannot be differentiated. - The trial did not include severe forms of suicidality. - Limited diversity (91% Caucasian) - Self-report outcomes - Small sample size
Agin-Liebes et al., 2020 [15] [22]	US	Long-term follow-up after RCT	NCT00957359	N = 15 (9 women), mean age 53 years (SD = 15.5) with cancer meeting DSM-IV criteria for an adjustment disorder or generalized anxiety disorder	Psilocybin (0.3 mg/kg) + psychotherapy	No	Reductions from baseline were observed in HADS Total, HADS Anxiety, HADS Depression, BDI, STAI-State, and STAI-Trait at 6.5 months, 3.2 years, and 4.5 years after treatment. Improvements from baseline were seen in FACIT-Sp at the 4.5-year follow-up.	- No serious adverse events	- A crossover design without a true control group cannot effectively assess long-term effects. - The effects of psilocybin and the psychotherapeutic session cannot be differentiated. - Limited diversity (94% non-Hispanic Caucasian) - Self-report outcomes - Small sample size
Grob et al., 2011 [28]	US	Randomized controlled trial	NCT00302744	N = 12 (11 women), age 36 to 58 years (mean and SD: NR) with cancer meeting DSM-IV criteria for secondary depression (acute stress disorder, generalized anxiety disorder, anxiety disorder due to cancer, or adjustment disorder with anxiety)	Psilocybin (0.2 mg/kg)	Niacin (250 mg)	Significant differences between the psilocybin-first and placebo-first groups were found in STAI-Trait at 1 and 3 months after the session. For BDI, differences between the groups were observed 6 months after the session.	- No serious adverse events - Side effects: minor heart rate and blood pressure elevations	- Self-report outcomes - Small sample size
Griffiths et al., 2016 [23]	US	Randomized controlled trial	NCT00465595	N = 51 (25 women), mean age 56.3 years (SD = 1.4) with cancer meeting DSM-IV criteria for secondary depression (dysthymic disorder, or adjustment disorder with anxiety and depressed mood, chronic) or anxiety disorders	Psilocybin (22 or 30 mg/70 kg) + psychotherapy	Psilocybin (1 or 3 mg/70 kg) + psychotherapy	Significant differences were found between the psilocybin-first and placebo-first groups in BDI, HADS Depression, and GRID-HAMD at 5 weeks after the first session, but not at 5 weeks after the second session. These effects persisted for 6 months. Significant differences were observed in HAM-A, and STAI-Trait at 5 weeks after the first session, but not at 5 weeks after the second session, with effects lasting for 6 months.	- No serious adverse events - Side effects: elevated systolic and diastolic blood pressure, nausea, vomiting, physical and psychological discomfort, anxiety, paranoid ideation, headache	- The placebo is pharmacologically active. The effects of psilocybin and the psychotherapeutic session cannot be differentiated. - Limited diversity (94% White race) - Self-report outcomes - Small sample size
Lewis et al., 2023 [44]	US	Non-randomized trial	NCT05557643	N = 12 (8 women), mean age 48.2 years (SD = 11.5) with cancer meeting DSM-V criteria for major depressive disorder, adjustment disorder with depressed mood, adjustment disorder with mixed anxiety and depressed mood	Psilocybin (25 mg) + psychotherapy	No	Reductions in HAM-D scores were observed at 2 weeks and 26 weeks after treatment. Improvements in five subscales of FACIT-Sp were apparent at 2 weeks after treatment.	- No serious adverse events - Side effects: headache, hypertension, hypotension, nausea, ventricular tachycardia, vomiting	- It lacks a control group. - The effects of psilocybin and the psychotherapeutic session cannot be differentiated. - Limited diversity (91.6% White race) - Self-report outcomes - Small sample size
Shnayder et al., 2023 [45]	US	Non-randomized trial	NCT04593563	N = 30 (21 women), mean age 56.1 years (SD = 12.4) with cancer meeting DSM-V criteria for major depressive disorder	Psilocybin (25 mg) + psychotherapy	No	Improvements in psycho-social-spiritual well-being, as measured by NIH-HEALS, were seen at 1 day, 1 week, 3 weeks, and 8 weeks after treatment.	- No serious adverse events - Side effects: headache, nausea, tearfulness, anxiety, euphoria, fatigue, mild impairment of psychomotor functioning	- It lacks a control group. - The effects of psilocybin and the psychotherapeutic session cannot be differentiated. - Limited diversity (80% Caucasian) - Self-report outcomes - Small sample size
Agrawal et al., 2023 [46]	US	Long-term follow-up after Non-randomized trial	NCT04593563	N = 30 (21 women), mean age 56.1 years (SD = 12.4) with cancer meeting DSM-V criteria for major depressive disorder	Psilocybin (25 mg) + psychotherapy	No	Half of the participants experienced complete remission of depressive symptoms by week 1, and this improvement was maintained for 8 weeks. Improvements in pain, demoralization, disability, and psycho-social-spiritual well-being were seen after treatment.	- No serious adverse events - Side effects: headache, nausea, mood altered, anxiety, fatigue, insomnia, paresthesia, time perception altered, dehydration, and mild impairment of psychomotor functioning	- It lacks a control group. - The effects of psilocybin and the psychotherapeutic session cannot be differentiated. - Limited diversity (80% Caucasian) - Self-report outcomes - Small sample size

NR Not reported, SD Standard deviation, HADS Hospital Anxiety and Depression Scale, BDI Beck Depression Inventory, STAI State-Trait Anxiety Inventory, FACIT-Sp Functional Assessment of Chronic Illness Therapy- Spiritual Well-being, HAM-D Hamilton Depression Rating Scale, GRID-HAMD GRID Hamilton Rating Scale for Depression, HAM-A Hamilton Anxiety Rating Scale, NIH-HEALS National Institutes of Health Healing Experience of All Life Stressors

Adverse events

Except for Ross et al. [43], who did not report any adverse events, the other six studies found no serious adverse events associated with psilocybin. Ross et al. [22], Griffiths et al. [23], and Grob et al. [28] reported that increased blood pressure and heart rate were the most commonly observed adverse events. Other frequently mentioned adverse events included headache, anxiety, nausea, and psychological discomfort. Lewis et al. [44] found that nausea was the most prevalent adverse events, affecting 41.7% of patients. Shnayder et al. [45] determined that headache and nausea were the most frequent adverse events, affecting 80% and 40% of the patients, respectively (Table 1).

Risk of bias

Three RCT studies [22, 23, 28] had some concerns regarding their quality scores. The quality assessment of Ross et al. [22] was also applicable to the long-term follow-up studies by Ross et al. [43], and Agin-Liebes et al. [15] (Fig. 2). Two non-randomized studies [44, 45] received low quality scores (Fig. 2).

Fig. 2.

Risk of bias (ROB) assessment of included randomized controlled studies based of ROB-2 (up) and non-randomized studies based of ROBINS-1 (down)

Synthesis of results

Placebo controlled analysis

The meta-analysis, summarized in Table 2 and Supplementary Figures S1–S7, evaluated the effects of psilocybin versus placebo on psychological outcomes in cancer patients. Two studies with 79 participants were included (40 psilocybin, 39 placebo). The BDI showed a significant reduction (SMD = − 2.87, 95% confidence interval [CI]: − 3.99 to − 1.76, p < 0.001; I² = 61.13). Similarly, the HADS-D revealed a strong effect (SMD = − 2.97, 95% CI: − 3.60 to − 2.33, p < 0.001; I² = 0.00). In contrast, the Hospital Anxiety and Depression Scale–Anxiety subscale (HADS-A) was non-significant (SMD = − 3.63, 95% CI: − 8.02 to 0.77, p = 0.11) with high heterogeneity (I² = 94.66). For anxiety measures, the STAI-S indicated a significant reduction (SMD = − 1.84, 95% CI: − 2.36 to − 1.32, p < 0.001; I² = 0.00), while the STAI-T showed a significant effect (SMD = − 4.70, 95% CI: − 8.19 to − 1.21, p = 0.01) but high heterogeneity (I² = 90.21). Quality of life (QOL) results were non-significant (SMD = 0.86, 95% CI: − 2.59 to 4.30, p = 0.63; I² = 67.03). Finally, the Death Transcendence Scale (DTS) demonstrated a significant positive effect (SMD = 0.89, 95% CI: 0.44 to 1.35, p < 0.001; I² = 0.00).

Table 2.

Meta-analysis of studies with placebo control

Variable	N of studies	N (case / control)	SMD (CI %95)	P-value	I2
BDI	2	79 (40/39)	-2.87 [-3.99, -1.76]	< 0.001	61.13
HADS-D	2	79 (40/39)	-2.97 [-3.60, -2.33]	< 0.001	0.00
HADS-A	2	79 (40/39)	-3.63 [-8.02, 0.77]	0.11	94.66
STAI-S	2	79 (40/39)	-1.84 [-2.36, -1.32]	< 0.001	0.00
STAI-T	2	79 (40/39)	-4.70 [-8.19, -1.21]	0.01	90.21
QOL	2	79 (40/39)	0.86 [-2.59, 4.30]	0.63	67.03
DTS	2	79 (40/39)	0.89 [0.44, 1.35]	< 0.001	0.00

BDI Beck Depression Inventory, HADS-D Hospital Anxiety and Depression Scale – Depression, HADS-A Hospital Anxiety and Depression Scale – Anxiety, STAI-S State-Trait Anxiety Inventory – State, STAI-T State-Trait Anxiety Inventory – Trait, QOL Quality of Life, DTS Death Transcendence Scale

Single arm analysis

Short term (2–5 weeks)

The meta-analysis presented in Table 3 (and Supplementary Material, Figure S8-21) summarizes the effects of psilocybin on various psychological outcomes in cancer patients, focusing on short-term follow-up (2–5 weeks). The analysis includes data from multiple studies, with the following key findings: BDI showed a significant SMD of -1.17 (95% CI: -1.73 to -0.61) across 52 participants from 3 studies, indicating a strong reduction in depressive symptoms (p < 0.001). The HADS-D and HADS-A also demonstrated substantial effects, with SMDs of -1.58 (95% CI: -2.07 to -1.08) and − 1.99 (95% CI: -2.52 to -0.146), respectively, both with p-values < 0.001 and no observed heterogeneity (I² = 0%). The STAI-S and STAI-T revealed SMDs of -1.17 (95% CI: -1.50 to -0.84) and − 1.34 (95% CI: -1.90 to -0.78), respectively, with significant reductions in anxiety symptoms across 82 participants from 4 studies, again with p < 0.001. In addition, the HAMA reported an impressive SMD of -2.20 (95% CI: -3.64 to -0.77), indicating severe anxiety reduction among 56 participants from 2 studies (p < 0.001), although this showed high heterogeneity (I² = 88.07). The Profile of Mood States (POMS) indicated a moderate effect with an SMD of -1.18 (95% CI: -2.05 to -0.31) and a p-value of 0.01, while the QOL measure yielded an SMD of 8.67 (95% CI: -2.09 to 19.42), which was not statistically significant (p = 0.11) and exhibited high heterogeneity (I² = 95.64). Notably, the FACIT-Sp showed a positive effect with an SMD of 2.58 (95% CI: 0.55 to 4.61) and p = 0.01, highlighting potential spiritual benefits from psilocybin therapy among cancer patients, while the DTS indicated a modest effect size of 0.51 (95% CI: 0.06 to 0.96) with p = 0.03, reflecting some positive psychological shifts post-treatment across the analyzed studies.

Table 3.

Single-arm meta-analysis with short-term follow-up (2–5 weeks)

Variable	N of studies	N of participants	SMD (CI %95)	P-value	I2	Begg/Egger tests
BDI	3	52	-1.17 [-1.73, -0.61]	< 0.001	43.48	> 0.99/0.77
HADS-D	2	40	-1.58 [-2.07, -1.08]	< 0.001	0.00	NA
HADS-A	2	40	-1.99 [-2.52, − 0.146]	< 0.001	0.00	NA
STAI-S	4	82	-1.17 [-1.50, -0.84]	< 0.001	0.00	> 0.99/0.72
STAI-T	4	82	-1.34 [-1.90, -0.78]	< 0.001	61.22	0.73/0.29
HAMA	2	56	-2.20 [-3.64, -0.77]	< 0.001	88.07	NA
POMS	2	38	-1.18 [-2.05, -0.31]	0.01	66.28	NA
QOL	2	40	8.67 [-2.09, 19.42]	0.11	95.64	NA
FACIT-Sp	3	52	2.58 [0.55, 4.61]	0.01	93.11	> 0.99/0.12
DTS	2	38	0.51 [0.06, 0.96]	0.03	0.00	NA

BDI Beck Depression Inventory, HADS-D Hospital Anxiety and Depression Scale – Depression, HADS-A Hospital Anxiety and Depression Scale – Anxiety, STAI-S State-Trait Anxiety Inventory – State, STAI-T State-Trait Anxiety Inventory – Trait, HAMA Hamilton Anxiety Rating Scale, POMS Profile of Mood States, QOL Quality of Life, FACIT-Sp Functional Assessment of Chronic Illness Therapy - Spiritual Well-Being, DTS Death Transcendence Scale

Long term (six months)

The meta-analysis presented in Table 4 (and Supplementary Material, Figure S22-32) evaluates the effects of psilocybin on various psychological distress measures in cancer patients, with a focus on long-term follow-up at six months. The analysis includes data from multiple studies, revealing significant findings across several variables. For the BDI, three studies involving 49 participants reported a SMD of -2.60 (95% CI: -5.03 to -0.17) with a p-value of 0.04, indicating a statistically significant reduction in depressive symptoms. The heterogeneity among studies was high, with an I² value of 94.49, suggesting considerable variability in outcomes. The Hospital Anxiety and HADS-D showed an even more pronounced effect, with two studies and 41 participants yielding an SMD of -3.56 (95% CI: -6.15 to -0.97) and a p-value of 0.01, also indicating significant improvement. In contrast, the STAI-S and STAI-T both demonstrated non-significant results with p-values of 0.20, despite high I² values of 97.12 and 98.30, respectively. In terms of quality of life and spiritual well-being, the QOL measure indicated a positive outcome with an SMD of 1.73 (95% CI: 1.11 to 2.36) and a p-value less than 0.001 across two studies involving 41 participants, reflecting a meaningful enhancement in patient quality of life post-psilocybin treatment. Similarly, the FACIT-Sp showed a substantial effect with an SMD of 3.02 (95% CI: 1.02 to 5.03), also statistically significant (p < 0.001). The Profile of Mood States (POMS) indicated significant improvements as well, with an SMD of -1.35 (95% CI: -1.87 to -0.83) and a p-value less than 0.001, while the HADS-A showed a strong reduction in anxiety symptoms with an SMD of -2.59 (95% CI: -3.60 to -1.57) and p < 0.001 across two studies involving the same participant as HADS-D.

Table 4.

Single-arm meta-analysis with long-term follow-up (6 months)

Variable	N of studies	N of participants	SMD (CI %95)	P-value	I2	Begg/Egger tests
BDI	3	49	-2.60 [-5.03, -0.17]	0.04	94.49	> 0.99/0.08
HADS-D	2	41	-3.56 [-6.15, -0.97]	0.01	89.30	NA
HADS-A	2	41	-2.59 [-3.60, -1.57]	< 0.001	60.56	NA
STAI-S	3	49	-2.14 [-5.39, 1.11]	0.20	97.12	> 0.99/0.22
STAI-T	3	49	-2.92 [-7.35, 1.52]	0.20	98.30	> 0.99/0.01
POMS	2	34	-1.35 [-1.87, -0.83]	< 0.001	0.00	NA
QOL	2	41	1.73 [1.11, 2.36]	< 0.001	29.37	NA
FACIT-Sp	2	41	3.02 [1.02, 5.03]	< 0.001	86.20	NA

BDI Beck Depression Inventory, HADS-D Hospital Anxiety and Depression Scale – Depression, HADS-A Hospital Anxiety and Depression Scale – Anxiety, STAI-S State-Trait Anxiety Inventory – State, STAI-T State-Trait Anxiety Inventory – Trait, HAMA Hamilton Anxiety Rating Scale, POMS Profile of Mood States, QOL Quality of Life, FACIT-Sp Functional Assessment of Chronic Illness Therapy - Spiritual Well-Being

Discussion

There is growing concern about existential, spiritual, and psychological status, including general anxiety disorder, panic attacks, and depression among patients suffering from cancer and their families [48–50]. Managing these conditions has been associated with higher life expectancy, increased social support, reduced pain, and higher rates of disease acceptance among patients [51, 52]. Our systematic approach improves completeness of evidence capture; however, the strength of inference remains limited by small samples and risk of bias. This comprehensive review highlights not only the psychological benefits but also the importance of evaluating depression, anxiety, and existential distress in an integrated manner.

The evidence of the efficacy of this psychedelic for treating resistant depression has grown recently [53–55]. Confirming although moderate level of heterogeneity, our results on placebo control RCTs showed a significant reduction in the BDI score of depression. Our results on short- and long-term effects of psilocybin also showed a statistically significant reduction in depressive symptoms according to lower BDI scores. A recent qualitative meta-analysis by Crowe et al. suggested that psilocybin could be subjectively effective in clinical conditions [56]. To a greater extent, the subjective experience of why patients suffer from depression could be related to the efficacy of this psychedelic medication. Our findings of significant effect on BDI scores show that psilocybin is not only a promising choice to treat post-traumatic depression, alcohol and other substance use disorders, or chronic diseases such as HIV infection, but it could be helpful to regulate cancer patients’ psychological distress [56–59]. Qualitative findings suggest psilocybin may foster acceptance of illness and enhance well-being by shifting patients’ perspectives on their cancer experience [56, 60]. Psilocybin seems to enable or stimulate the ability to transform cancer-related experiences into altered perceptions, resulting in better acceptance as well as acknowledgment of their condition and promisingly improved well-being. Similarly, a qualitative study on twenty patients suffering treatment-resistant post-traumatic depression showed that psilocybin provided cathartic experiences as well as feelings of surrendering to trauma memories, leading to a sense of letting go of pain experiences and a long-lasting feeling of openness [61]. Depression, as a state of loneliness and disconnection, is also found in cancer patients [62]. The feeling of being different, being willing to connect but unable to, and sudden interruption of normal life, promote depression [63]. Psilocybin was proven to provoke the feeling of connection to self and one’s emotions, spreading to the environment [56, 61]. A clinical trial on cancer patients confirmed previously reported effects of psilocybin on clinical, self, and family-rated depression [23]. Moreover, authors also demonstrated improved death acceptance, life meaning, anxiety, and optimism caused by high-dose psychedelics. Psychological flexibility of psilocybin is defined as the ability to contact the present time consciously and navigate experiences while concurrently motivating the ability to decide and change [55, 64]. This effect has been associated with promising therapeutic effects on anxiety, alcohol consumption, and posttraumatic stress disorders [65, 66]. Psychological flexibility as a potential motivating factor to consciously decide against alcohol abuse could also affect mood disturbances and depression among cancer patients. Psilocybin could also help the patient suffering from cancer to understand the importance of being and the connection with others [67].

In line with promising outcomes of psilocybin on BDI score, results on placebo-controlled trials of HADS-D determined significant improvement in the treatment group with no heterogeneity. Nevertheless, HADS-A analysis showed no significant change (SMD of -3.63; 95% CI: -8.02 to 0.77, P = 0.11), which could be explained by high heterogeneity. HADS-D and HADS-A both demonstrated considerable effects on depressive symptoms, assessing short- and long-term follow-up results in studies with a single-arm design. These disparities could be explained by the high degree of variation among studies. In addition, it has been proven that although exceedingly high safety profile and low risk, psilocybin is functional only when attentively considering the conduct of set and setting [68, 69]. Set refers to the psychological preparation of the patient, while setting addresses the environment. We suggest that the acceptance of the importance of psychological therapy as the set, and more exclusively, the stage of the cancer, the metastasis, the treatment strategy, the response of patients’ body to complications associated with chemotherapy, the socioeconomic status of the patients, the same familial experience as well as patients’ familial and emotional support, could all be involved in the environment behind the hallucinogenic therapy. Further studies should focus on factors ameliorating the effect of psilocybin treatment. Moreover, the efficacy of psilocybin was associated with acute personal experience of the psychedelic in addition to the plasma levels of the active metabolite among alcohol dependents [70]. In this regard, besides further investigations on proper loading doses and plasma levels, qualitative studies assessing the acute experience of psilocybin and the associations with cancer life disturbances, drug doses, and therapeutic results seem necessary. Additionally, consistent with emerging evidence, the intensity and quality of subjective psychedelic experiences appear to predict clinical outcomes [71]. Although our included trials provided limited data, future research should systematically capture these experiences, as they may mediate psilocybin’s therapeutic impact and explain inter-study variability in psychological outcomes.

Although high heterogeneity, psilocybin significantly reduced STAI-trait scores for anxiety in both short-therapeutic periods, and placebo-controlled RCTs with SMDs of -4.70 (95% CI: -8.19 to -1.21) and − 1.34 (95% CI: -1.90 to -0.78), respectively. Nonetheless, STAI-trait scores demonstrated non-significant results. Included studies were also evaluated for STAI-S scores, suggesting substantial improvement of the psychedelic on anxiety among cancer patients, both compared to placebo and after short-term follow-up. Hendricks et al. found that lifetime psilocybin consumption was considerably associated with a large reduction in psychological distress [72]. In an investigation on men with prostate cancer, the degree of trait anxiety was correlated with state anxiety, revealing the importance of its role in participants’ psychological well-being [73]. Thus, the lower the anxiety, the higher the well-being status. Our findings indicated a significant increase in spiritual well-being and long-term quality of life among cancer patients by taking psilocybin. This simply clarifies the tight relation between anxiety, well-being, and quality of life.

A primary distinction between the STAI and HADS lies in their assessment of somatic versus psychological aspects of anxiety. The STAI, while assessing psychological anxiety, also captures somatic features such as bodily tension and restlessness. In contrast, the HADS, developed for medical settings, minimizes somatic items and emphasizes cognitive and emotional symptoms of anxiety and depression. Given that psilocybin is expected to exert longer-lasting effects on psychological rather than somatic aspects, sustained changes are anticipated on the HADS-A rather than the STAI-T.”

The exact mechanism of psilocybin in treating depression and anxiety is unclear. Its antidepressant effect is linked to rapid 5-HT receptor activation [74, 75], increased brain-derived neurotrophic factor independent of other treatments [76], dose-dependent neurogenesis [77], and reduced interleukin-6 levels [78]. Nonetheless, using novel therapy to address cancer-associated complications needs extra attention and investigations according to the nature of cancer itself. First, regarding the limited data on this treatment strategy among cancer individuals, while antidepressants and anxiolytics are functional and the majority of patients still benefit from standard therapeutics, unknown adverse events grow as an immense concern, although psilocybin showed a symptom non-worsening nature [79, 80]. Second, immunomodulation of cancer cells is the major therapy to inhibit cancer proliferation. Serotonin 5-HT2A receptor, as the main target of serotonergic hallucinogens such as psilocybin, is also known to be involved in cell proliferation as well as regulating immune response to inflammation caused by cancer [81, 82]. In vivo studies in mice showed tumor growth in E0771 breast cancer, while in vitro assays demonstrated cell death [83]. To date, in vivo studies of the effect of psilocybin on immunomodulation of cancer patients remain vague. It might be necessary to expand evaluations to assess the influence of psychedelics on cancer proliferation. Third, even if psilocybin has promising therapeutic potential, its use in clinical settings requires thorough ethical analysis. Responsible psilocybin integration into therapeutic settings requires addressing possible dangers and putting in place an improved informed consent procedure [84]. Moreover, the therapeutic touch involved in psilocybin sessions is an ethical dilemma. Patients’ preferences may change during an encounter; hence, therapists should handle such situations with care and, at all times, respect the patients’ freedom and comfort.

Finally, psilocybin is an emerging area of research. The mechanism and effects remain vague and there yet to be discovered. More importantly, the clinical effectiveness is according to the limited number of controlled trials. Although fragile, the benefits of this pharmaceutical family reported in depression and anxiety were first approved by this meta-analysis on randomised and non-randomized trials among cancer patients. Cancer is not only a chronic disease, but mainly a sudden trauma that turns patients’ lives inside out. Addressing depression and anxiety among patients and their families is one important priority. A few numbers of studies on this growing area yield the need for further evaluations to not only confirm the feasibility and the efficacy of psilocybin, but also provide standard protocols for preparing sets and settings of therapy, identifying and managing probable adverse events, and last but not least, determine the efficacy of combination therapies among cancer patients.

Recently, Bader et al. conducted a systematic review and meta-analysis on psilocybin in adults with advanced cancer, reporting improvements in anxiety, quality of life, pain, and existential well-being across 7 studies with 132 participants [37]. Authors showed that psilocybin-assisted therapy reduced the pooled mean anxiety levels measured by the STAI scale; 35.15 (95%CI: 32.28–38.01) after 4 to 5 months, and 33.06 (95%CI: 28.73–37.40) after 6 to 6.5 months post-administration [37]. They focused only on a small number of studies and participants, and did not report short- and long-term outcomes. Additionally, they evaluated a limited set of clinical outcomes without systematically assessing both anxiety and depression using multiple validated measures. While confirming the significant relief of psilocybin on anxiety levels of cancer patients, the current study had multiple strengths and provided further information. First, we categorized studies regarding the design (placebo-controlled, short, and long-term follow-up). Second, we also evaluated depression, which not only accompanies anxiety but also exacerbates the patient’s condition. Third, regarding both psychological disorders, to reduce disparities, varied measuring scales were pooled separately.

This review has several important limitations. First, the included trials were few and small, with generally high or unclear risk of bias; strong subjective effects of psilocybin make blinding difficult, and preregistered protocols or analysis plans were inconsistently reported, all of which can affect reliability and generalizability [85]. Although our sample is larger than in Bader et al. [37], the overall evidence base remains limited. Second, heterogeneity was substantial across studies—in populations, comparators, follow-up windows, and outcome instruments (HADS, BDI, STAI, etc.). Because these tools capture related but non-identical constructs, we analyzed them separately to preserve construct fidelity; however, this reduces precision and complicates synthesis. Third, many estimates derive from single-arm pre–post data, which are vulnerable to regression to the mean, spontaneous improvement, and selection biases; such findings should be viewed as hypothesis-generating. Fourth, most trials combined psilocybin with psychotherapy in specialized settings, and concurrent cancer treatments varied; drug effects cannot be disentangled from psychotherapeutic or contextual factors. Limited data isolate medication-only effects (e.g [28]). , , and group-based psychotherapeutic additions may further limit comparability [86]. Fifth, external validity is restricted: all studies were conducted in the United States with relatively homogeneous samples (predominantly female), so applicability to men and to more diverse populations is uncertain. Finally, adverse-event reporting and power to detect uncommon harms were limited, and formal assessment of publication bias was often infeasible due to the small number of studies.

Conclusion

Psilocybin-assisted therapy may help reduce depressive symptoms in cancer patients, with mixed effects on anxiety. This meta-analysis synthesizes randomized and non-randomized trials evaluating depression and anxiety after treatment. Across short- and long-term follow-up, depressive symptoms generally decreased, whereas anxiety findings varied by instrument and timepoint; however, significant heterogeneity and small samples limit generalizability. Psychological preparation and treatment environment may influence observed effects of this psychedelic-assisted therapy. Despite limitations, including few trials, limited geographic diversity, and challenges with blinding/expectancy, the accumulating evidence supports further, rigorous investigation of psilocybin for cancer-related psychological distress. Future large, longitudinal studies should incorporate robust blinding and preregistration, assess moderators (e.g., chemotherapy status), systematically evaluate adverse events and potential drug–drug interactions, and compare psychotherapy components and combination pharmacotherapies. Preclinical work may further clarify biological effects, including on cancer cell behavior.

Authors’ contributions

The initial search was conducted by SM and AG, while RM and MP identified the subject. RM, YK, KJ and MP collaboratively wrote the first draft, with input from SM and AG. The final version was edited by JA and SN, and RM handled the analysis. All authors, including RM and MP, oversaw the process and unanimously approved the publication.

Funding

Not applicable.

Data availability

The text and supplementary materials provide all necessary information; additional details can be requested via email from the corresponding author.

Declarations

Ethics approval and consent to participate

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Not applicable.

Competing interests

The authors declare no competing interests.