Psilocybin and Depression

Psilocybin and Depression

Depression affects approximately 280 million people worldwide, making it a significant public health issue (1). Symptoms described in the Diagnostic and Statistical Manual of Mental Disorders include sadness, sleep disturbances, changes in appetite and energy levels, suicidal ideation, anhedonia, and diminished interest (2). A combination of both psychotherapy and antidepressants seems to be the most efficient way to reduce these symptoms (3). However, most of these pharmacological treatments have a low rate of efficacy and response, with some adverse secondary effects, such as feelings of numbness and detachment, sexual difficulties, reduction in positive feelings, weight gain, among others (4), taking several weeks to produce positive reactions (5).

Treatment-resistant depressive disorder (TRD) lacks a universally accepted definition, but Nierenberg and Amsterdam (1990) define it as a condition in which at least two standard treatments fail (6). With the rising prevalence of mental disorders and the limitations of conventional treatments, researchers have been exploring the potential of psychedelics since the 1950s. These substances appear to address some challenges associated with traditional antidepressants.

First, psychedelics tend to produce fewer and more transient side effects, such as nausea, hypertension, and increased heart rate, which are generally well-tolerated and rarely persist beyond the duration of the substance’s effects. Additionally, while antidepressants typically require long-term use to achieve therapeutic outcomes, psychedelic-assisted therapy has demonstrated positive results after only a few sessions (7).

Moreover, psychedelics appear to promote neuroplasticity—the nervous system’s ability to restructure itself and adapt to changes in its environment—a process crucial for learning and memory (8). This neuroplasticity may contribute to meaningful improvements in individuals with various mental health conditions.

Building on this, when combined with psychotherapy, psychedelics show promise in treating depression, anxiety, addiction, and post-traumatic stress disorder (PTSD) (9).

Among serotonergic psychedelics—such as psilocybin, LSD, and DMT—psilocybin, a naturally occurring tryptamine found in certain mushroom species (10), stands out as a particularly promising option. Research indicates its efficacy in reducing depressive symptoms is comparable to escitalopram, a widely prescribed antidepressant (3). Psilocybin interacts with serotonin receptors, altering brain dynamics and functional connectivity (11), as well as visual and auditory distortions, altered consciousness, and shifts in perception of self, time, and environment (3). Psilocybin has a low toxicity profile, minimal adverse effects, and low potential for abuse, making it one of the safest psychedelics studied (11). Alongside this, psilocybin seems to provoke mystical experiences, which can be defined as “loss of ego boundaries and profound feelings of personal meaning and spiritual significance” (3). It is shown that the occurrence of this kind of experience is related to long term positive changes, such as an increased openness, and an improvement of the depressive symptoms (12).

Psilocybin assisted therapy

            The majority of clinical trials using psychedelic assisted therapy is based on the same model, with a few preparation sessions, followed by the dosage sessions, finishing with the integration. Based on The Yale Manual for Psilocybin-assisted Therapy of Depression (13), the first sessions of preparation are meant for building the alliance with participants, learn about their background, and educate them on the psychedelic process. Therapists also address expectations for the medication session, review practical details like session length and music, set interaction boundaries, and discuss safety protocols. The dosing sessions usually last for 8 hours, and occur in a supportive, carefully prepared environment, encouraging inward focus and emotional exploration. Therapists create a warm, inviting space with music and eye masks, maintaining a non-directive presence, offering support and grounding techniques as needed. Participants are guided to approach their experiences with openness and curiosity, even when facing challenging emotions. Safety protocols ensure physical and emotional well-being, allowing the session to facilitate deep insights and shifts in perspective. Lastly, the integration sessions emphasize reflection on the participant’s experience, making use of their insights, and encourage to adopt behaviors with the goal of overcoming depression.

Efficacy

Several studies highlight psilocybin’s rapid and long-lasting effects on depressive symptoms. Dawood Hristova and Pérez-Jover (2023) and Johnson and Griffiths (2017) found reductions in depression and anxiety symptoms in some cases as early as one day after administration, with effects persisting over time (7, 14). Griffiths et al. (2016) demonstrated improvements in quality of life, life meaning, and death acceptance among patients with life-threatening cancer (15). Moreover, Griffiths et al. (2006) reported significant positive changes in attitudes and behaviors among individuals who had mystical experiences induced by psilocybin (16).

When comparing with ketamine-assisted therapy, both psilocybin and ketamine offer rapid and transformative approaches to treat depression by acting on neuroplasticity and altering neural circuits (17). However, ketamine produces faster antidepressant effects, often providing relief within hours, making it especially effective for acute conditions such as severe depressive episodes and suicidal ideation. In addition, ketamine’s shorter duration of action, typically lasting 45 minutes to 1 hour, makes it more adaptable for use in clinical settings, where integrated into traditional psychiatric care​ (18).

These studies emphasized the importance of a supportive therapeutic alliance and controlled, comfortable environments to ensure positive outcomes.

Conclusion

Psychedelic-assisted therapy represents a paradigm shift in the treatment of depression, particularly for individuals unresponsive to traditional pharmacological interventions (9). Psilocybin is currently in Phase 3 trials for treatment-resistant depression, bringing us closer to a revolutionary medical breakthrough (19).

While psilocybin-assisted therapy is not yet legally available at Clinica Synaptica, our commitment to research ensures we remain at the forefront of innovative mental health treatments.

References

1. World Health Organization (WHO). Depressive disorder (depression). Available from: https://www.who.int/news-room/fact-sheets/detail/depression [Accessed 2024 Nov 21].

2. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Washington, DC: American Psychiatric Publishing; 2013.
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13. Guss, J., Krause, R., & Sloshower, J. (2020). The Yale manual for psilocybin-assisted therapy of depression (using acceptance and commitment therapy as a therapeutic frame)

14. Johnson MW, Griffiths RR. Potential therapeutic effects of psilocybin. Neurotherapeutics. 2017;14:734–40.
15. Griffiths RR, Johnson MW, Carducci MA, Brandt AL, Richards WA, Richards BD, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol. 2016;30(12):1181–97.
16. Griffiths RR, Richards WA, McCann U, Jesse R. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology. 2006;187(3):268–83.
17. Psiuk D, Nowak EM, Dycha N, Łopuszańska U, Kurzepa J, Samardakiewicz M. Esketamine and Psilocybin—The Comparison of Two Mind-Altering Agents in Depression Treatment: Systematic Review. Int J Mol Sci. 2022;23(19):11450. doi:10.3390/ijms231911450
18. Wolfson P, Vaid G. Ketamine-assisted psychotherapy, psychedelic methodologies, and the impregnable value of the subjective—a new and evolving approach. Front Psychiatry. 2024;15:1209419. doi:10.3389/fpsyt.2024.1209419

19. Rucker JJ. Psilocybin therapy for depression. A good trip? J Ment Health. 2023;32(1):1–2.