Major depression, also known as major depressive disorder, is a common and debilitating illness that profoundly affects mood, cognition, and daily functioning. It manifests as persistent sadness, a loss of interest in usually pleasurable activities, and various physical and cognitive symptoms such as sleep disturbances, severe fatigue, and recurring negative thoughts. Its impact on quality of life is substantial, and without adequate management, it can lead to serious complications, including an increased risk of suicide. Diagnosis is based on precise clinical criteria, and initial treatment typically combines pharmacological and psychotherapeutic approaches tailored to the patient’s specific needs.
Standard pharmacological treatments for major depression primarily rely on the use of antidepressants, whose effectiveness has been widely demonstrated. Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, sertraline, and escitalopram, or serotonin-norepinephrine reuptake inhibitors (SNRIs), are often prescribed as first-line treatments due to their efficacy and good tolerability profile. The choice of treatment is based on an individualized assessment that considers the patient’s history, symptom severity, and potential comorbidities to optimize efficacy while minimizing risks.
Both antidepressants and psychotherapy are more effective than a placebo in treating major depression, with comparable efficacy at the beginning of treatment. For instance, a meta-analysis—a statistical review combining multiple studies on a similar issue—of four studies involving 775 participants found that cognitive behavioral therapy (CBT) alone was as effective as a second-generation antidepressant (such as an SSRI) in alleviating symptoms. Approximately 54% of patients in the CBT group and 55% in the antidepressant group experienced improvement, while 41% in the CBT group and 44% in the antidepressant group achieved complete remission. (1)
Another meta-analysis of 37 trials involving more than 8,400 participants with major depression showed higher remission rates at six weeks among those treated with fluoxetine or venlafaxine compared to placebo (43% vs. 29%; OR = 1.82, 95% CI: 1.66–2.00). Antidepressant treatment was effective in both mild (50% vs. 37% remission) and severe (38% vs. 25% remission) cases. (2)
These analyses highlight that all available treatments for major depression result in remission in fewer than 50% of cases. In this context, alternative treatment avenues must be explored.
Psilocybin as a Potential Alternative Treatment
Psilocybin, a hallucinogenic compound extracted from mushrooms commonly known as "magic mushrooms," is gaining increasing interest as an alternative treatment. However, few studies have directly compared its effectiveness with that of traditional antidepressants. This clinical study was conducted to evaluate the effects of psilocybin compared to escitalopram in the treatment of major depression.
Study Design
This clinical trial was conducted on 59 patients suffering from moderate to severe depression, as measured by the Hamilton Depression Rating Scale (HAM-D). Participants were between 18 and 80 years old and had suffered from depression for several years. They were required to discontinue any depression medication two weeks before the study's start.
The study lasted six weeks and was a randomized, controlled, double-blind trial, meaning that participants were randomly assigned to one of two groups, and neither they nor the researchers knew which treatment they were receiving.
First group: Received two doses of 25 mg of psilocybin administered three weeks apart, along with a daily placebo.
Second group: Received two doses of 1 mg of psilocybin (too low to have a significant effect) three weeks apart and a daily treatment of escitalopram, starting at 10 mg and increasing to 20 mg after three weeks.
All participants received structured psychological support throughout the study. Initially, a third placebo-only group was planned, but it was ultimately excluded.
Exclusion Criteria:
The study had strict exclusion criteria. Participants could not have a current or past diagnosis of a psychotic disorder, nor have an immediate family member with such a disorder. Significant medical conditions such as diabetes, epilepsy, severe cardiovascular disease, or liver/kidney failure could also disqualify a patient. A history of suicide attempts requiring hospitalization or past manic episodes were additional exclusion criteria. Patients who had previously taken escitalopram were also excluded.
Results
The primary efficacy measure was the 16-item Quick Inventory of Depressive Symptoms (QIDS-SR-16), a scale ranging from 0 to 27 points, where higher scores indicate more severe depression. Scores were compared from the start of the study to the six-week follow-up.
Both groups showed symptom improvement.
The average reduction in depression score was -8.0 in the psilocybin group vs. -6.0 in the escitalopram group.
After analysis, this difference was not statistically significant, meaning that, at best, psilocybin is equivalent in effectiveness to escitalopram.
However, secondary outcomes showed a trend favoring psilocybin:
70% of psilocybin patients had a 50% or greater improvement in symptoms, compared to 48% in the escitalopram group.
57% of psilocybin patients achieved full remission, compared to 28% in the escitalopram group.
Despite these promising trends, the statistical analysis did not account for the risks of multiple comparisons, meaning these results should be interpreted with caution.
Analysis
Side Effects
Side effects were generally comparable between groups.
Escitalopram was associated with increased anxiety and dry mouth, while the main side effect of psilocybin was transient headaches within 24 hours of administration.
Psilocybin patients reported improved emotional experiences, including a better ability to cry, feel compassion, experience intense emotions, and enjoy pleasure.
No severe side effects were reported.
Strengths and Limitations
The study’s rigorous protocol (randomized, controlled, and double-blind) minimizes errors and biases.
Direct comparison of psilocybin with a standard antidepressant is a step forward in evaluating alternative depression treatments.
A major limitation is the study’s short duration, as escitalopram may take up to 12 weeks to reach full effect.
The exclusion of a placebo group makes it harder to isolate the true effect of psilocybin.
Participants mostly preferred psilocybin before the study, which may have introduced bias.
Impact of Treatment Expectations
A secondary analysis examined the role of treatment expectations in influencing effectiveness. Results showed:
For individuals with low expectations of escitalopram, psilocybin was significantly more effective.
For those with high expectations of escitalopram, there was no significant difference between treatments.
This finding underscores the psychological component of treatment efficacy and the importance of properly informing patients.
This study suggests that psilocybin may be at least as effective as escitalopram, with potential advantages in certain measures and a similar safety profile. For individuals with positive expectations of psilocybin, this treatment could be a highly promising option. However, rigorous patient selection, close supervision, and structured psychological support are essential to ensure safety, as misuse could lead to adverse effects like hallucinations. Although these results are promising, larger and longer-term studies are needed to confirm psilocybin’s effectiveness and explore its potential as an alternative to standard antidepressants.
Références
1- Gartlehner G, Dobrescu A, Chapman A, et al. Nonpharmacologic and Pharmacologic Treatments of Adult Patients With Major Depressive Disorder: A Systematic Review and Network Meta-analysis for a Clinical Guideline by the American College of Physicians. Ann Intern Med 2023; 176:196.
2 - Gibbons RD, Hur K, Brown CH, et al. Benefits from antidepressants: synthesis of 6-week patient-level outcomes from double-blind placebo-controlled randomized trials of fluoxetine and venlafaxine. Arch Gen Psychiatry 2012; 69:572.