Psychotherapy with Psilocybin for Depression: Systematic Review

Depression is a leading global health concern, affecting millions worldwide and resulting in substantial morbidity and mortality. Despite existing pharmacological treatments, many individuals experience limited efficacy, adverse effects, and poor adherence. This necessitates exploring novel and effective therapeutic interventions. Psilocybin, a naturally occurring compound with serotonergic effects, has shown promise in treating various mental health disorders, including depression. This systematic review investigates the evidence for the efficacy of psilocybin-assisted psychotherapy for depression, aiming to assess its potential as a novel treatment modality given the significant unmet clinical need.

The review highlights existing literature supporting the efficacy of psilocybin for depression, citing studies which have demonstrated positive results in treatment-resistant depression and in patients experiencing depressive symptoms related to cancer. Previous research also notes the limited efficacy and high rates of non-response associated with traditional antidepressant treatments, further motivating the exploration of alternative therapies such as psilocybin-assisted psychotherapy.

A literature search across ProQuest, PsycInfo, PubMed, ScienceDirect, and Scopus databases in April 2022 was conducted using keywords such as "psilocybin" and "depress*," along with synonyms and Boolean operators. The search was limited to titles and included studies published in English or Spanish. Inclusion criteria focused on research articles investigating psychological treatments supplemented with psilocybin for depression, without limitations on clinical trial type or patient population. Exclusions included theses, reports, book chapters, study protocols, descriptive articles, reviews, and studies that focused solely on pharmacological treatment or spiritual experiences without measuring psychological variables. The PRISMA guidelines were followed. Eighty-eight initial studies were identified, and eight met the final inclusion criteria after screening titles, abstracts, and full texts. Data extraction from included studies involved documenting country, objective, condition, design, participants, treatment, dose, measurement instruments, results, and conclusions. A PRISMA flow diagram visually represented this selection process.

Eight studies were included in the final analysis. All studies focused on psilocybin therapy for depressive disorder, with some addressing treatment-resistant depression or depression related to cancer. Five studies employed a randomized controlled design, with three being double-blind and two crossover studies. Sample sizes ranged from 12 to 59 participants, with a male predominance in most studies. Treatment involved preparatory sessions to establish a therapeutic alliance, followed by two psilocybin dosing sessions (6–8 h each) in a supportive environment with music therapy or psychotherapy. Integration sessions followed each dose. Psilocybin doses ranged from 10 mg to 30 mg/70 kg. The most commonly used dose was 25 mg. Placebo doses of 1 mg/70 kg or 250 mg niacin were employed in some double-blind studies. Evaluation measures primarily focused on depressive symptoms, using instruments such as the Beck Depression Inventory (BDI), Quick Inventory of Depressive Symptoms (QIDS), and the Hamilton Depression Rating Scale (HAM-D). All studies showed significant reductions in depressive symptoms after psilocybin treatment, with improvements observed as early as one day or one week post-dose, and lasting up to 12 months. Moderate/high doses were significantly more effective than placebo or low doses. Adverse effects were primarily mild and transient (headaches, dizziness, nausea, tachycardia) and did not hinder treatment. One comparative study with escitalopram found no significant difference between treatments at six weeks, although psilocybin treatment showed a more rapid onset of effect and potentially better adherence due to less frequent dosing.

The findings suggest that psilocybin-assisted psychotherapy is a promising approach to treating depression, particularly treatment-resistant depression, due to its rapid onset of action and sustained efficacy, contrasting with the slower and less predictable effects of conventional antidepressants. The significant role of the therapist is emphasized, focusing on the importance of building a therapeutic alliance before, during, and after psilocybin sessions. The supportive and non-directive approach of the therapists facilitated the integration of the psychedelic experience, leading to sustained positive changes. The study also highlights the potential significance of spiritual experiences in the therapeutic process, although further research is needed to definitively establish this relationship. While the current evidence is promising, more high-quality studies are needed to establish the long-term effects and the optimal parameters of psilocybin-assisted psychotherapy for depression, including the most effective types of psychotherapy to combine with psilocybin.

Psilocybin-assisted psychotherapy shows promise as a novel treatment for depression, demonstrating rapid and sustained symptom reduction in several studies. The importance of a strong therapeutic alliance and the potential role of spiritual experiences warrant further investigation. Despite the limited number of studies and geographical bias, the findings suggest psilocybin could revolutionize treatment approaches for depression and other mental health disorders, necessitating further research with rigorous methodologies to confirm its efficacy and safety.

The review's limitations include the small number of available studies, a geographical bias (primarily US and UK), and a lack of population representativeness (imbalance of genders and limited information on participant substance use histories). Many studies were conducted by the same researchers, limiting the generalizability of findings. Furthermore, the potential for expectancy bias in some studies due to the lack of perfect blinding procedures also needs to be considered in interpreting results. Future studies should address these limitations using larger, more diverse samples, robust blinding, and controlled comparisons with different types of psychotherapy.