Danielle B Rodrigues

doi:10.19080/JCMAH.2024.13.555852

Review Article

Use of Psilocybin in the Treatment of Mental Disorders: Systematic Review of Clinal Trials

Danielle B Rodrigues*, Victor HA Santos and Renato GC Leça

Faculdade de Medicina do ABC, Santo André, São Paulo, Brasil

Submission: August 01, 2024; Published: September 17, 2024

*Corresponding author: Danielle Rodrigues Faculdade de Medicina do ABC, Rúa Monteiro lobato, 61 - bairro dos casas, SÃ£o Bernardo do Campo -SP, Brazil

How to cite this article: Danielle B R, Victor HA S, Renato GC L. Use of Psilocybin in the Treatment of Mental Disorders: Systematic Review of Clinal Trials. J Complement Med Alt Healthcare. 2024; 13(1): 555852. DOI: 10.19080/JCMAH.2024.13.555852

Abstract

Title: Use of psilocybin in the treatment of mental disorders: systematic review of clinical trials.

Objective: To evaluate the high-impact evidence on the neurobiology, efficacy, safety, and feasibility of using psilocybin in the treatment of mental disorders such as depression, anxiety, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), smoking, and alcoholism.

Method: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a comprehensive search in the PubMed database up to December 2023. We used the following MeSH terms: “psilocybin AND mental health”, “psilocybin AND psychiatric disorders”, “psilocybin AND PTSD”, “psilocybin AND depression”, “psilocybin AND anxiety”, “psilocybin AND smoking”, “psilocybin AND tobacco”, “psilocybin AND alcohol”, “psilocybin AND addiction”, “psilocybin AND compulsive disorder”. We applied the “randomized controlled trial” and “clinical trial” filters to focus on the most scientifically impactful trials. We included randomized, open-label or double-blind clinical trials conducted on humans in a clinically controlled environment. We excluded duplicates, animal studies, healthy volunteers, recreational use analyses, secondary analyses, microdose studies, studies unrelated to the review topic, and those without full-text access. Two independent reviewers screened the titles, abstracts, and full texts of the identified studies, with a third reviewer assisting in the discussion and analysis of the evidence. We extracted relevant data from the 18 included studies and compiled them in a table, and also evaluated the risk of bias using the Rob2.0 (Revised Cochrane risk-of-bias tool for randomized trials) criteria, even though not all articles were randomized.

Results: The review of the 18 clinical trials, including 9 randomized and 9 open-label, showed that the administration of one or two doses of psilocybin (10-30 mg/70 kg) in a controlled setting results in significant therapeutic effects from the first day post-session. There was a substantial and lasting reduction in depressive symptoms, with benefits persisting for up to 12 months. Higher doses (25-30 mg/70 kg) were more effective in increasing positive feelings, reducing negative feelings, and improving patients’ anxiety and functionality. The psilocybin experience was often described as transformative, promoting positive changes in self-knowledge, mood, relationships, and spirituality, facilitating a re-evaluation of beliefs and a new perspective on life. Neurobiologically, these effects are attributed to the stimulation of serotonergic receptors, changes in cerebral blood flow in the amygdala, and alterations in the integrity of the default mode network, accompanied by mood improvements. Cancer patients at the end of life reported greater acceptance and willingness to face emotions, including negative ones, resulting in better quality of life. Psilocybin also showed promising therapeutic effects in the treatment of substance abuse such as alcohol and tobacco, obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD). Most smokers reported changes in perspective, with an abstinence rate of over 60% after one year. In alcoholic patients, there was a significant reduction in days of excessive alcohol consumption compared to placebo. A single clinical trial on OCD was found, showing a significant reduction in symptoms 24 hours after the administration of the doses, however, we did not have access to the full text. Although there are no clinical trials evaluating the efficacy of psilocybin in the treatment of PTSD, there is potential due to its action on the default mode network. The substance was well tolerated, with transient side effects such as increased blood pressure, heart rate, headache, and nausea. A case of passive suicidal ideation and some reports of transient fear or anxiety were observed, but no persistent psychotic disturbances or hallucinations. However, there is a high risk of bias, as most studies were conducted on small and homogeneous samples, mostly composed of white individuals with a high level of education. The lack of control groups and possible selection bias due to the exclusion of patients with psychiatric comorbidities limit the applicability of the results to a specific population. Only 7 studies were double-blind, and the effectiveness of blinding is questionable due to the perceptibility of the effects of psilocybin, compromising the control of factors such as patient expectations and the quality of the therapeutic relationship.

Conclusion: The combination of psilocybin with psychotherapy appears promising in the treatment of depression, end-of-life anxiety, smoking, and alcoholism, often resistant to conventional treatments. There is potential to improve OCD and PTSD symptoms, despite less evidence. Psilocybin can increase emotional sensitivity and acceptance, providing participants with insights and promoting neuroplasticity for the restructuring of ideas and behaviors. Participants reported lasting positive effects, such as feelings of gratitude, well-being, and openness to new experiences. However, more double-blind randomized clinical trials with larger samples are needed to confirm its long-term efficacy and safety.

Keywords: Psilocybin; Mental disorders; Treatment-resistant depression; Anxiety; End-of-life Anxiety, Post-Traumatic Stress Disorder (PTSD); Obsessive-Compulsive Disorder (OCD); Substance use Disorder; Smoking; Alcoholism

Abbreviations: PTSD: Post-Traumatic Stress Disorder; OCD: Obsessive-Compulsive Disorder; BDNF: Brain-Derived Neurotrophic Factor; TrkB: Tropomyosin receptor kinase B; PAP: Psilocybin-Assisted Psychotherapy; ECT: Electroconvulsive Therapy; CBT: Cognitive-Behavioral Therapy; Y-BOCS: Yale-Brown Obsessive Compulsive Scale; SSRIs: Selective Serotonin Reuptake Inhibitors

Introduction

From Cultural use to Science: a Historical Overview

Psilocybin is the substance responsible for the psychedelic effects of “magic mushrooms”, being found in more than 180 species of psilocybin-containing mushrooms. Several cultures, mainly the Aztecs, used these mushrooms to learn and supposedly communicate with the dead. In the 16th century, a Spanish Franciscan friar named Bernardino de Sahagún wrote a manuscript based on ethnographic research on Aztec culture. He mentioned the terms “teonancatl” and “flesh of the gods” to refer to the “sacred mushrooms of Mesoamerica”. However, it was only in the 1930s that researchers from Harvard University found the manuscript, when they traveled to Huautla, Mexico, to witness mushroom ceremonies and bring specimens for research in the United States, which were interrupted by the context of the Cold War.

In the 1950s, mycologists Gordon and Valentina Wasson received a letter describing the ritual use of the substance by Mesoamericans in the 16^thcentury. Intrigued, they began to search for the mushrooms until they were invited to participate in a ceremony in Huautla de Jiménez, Oaxaca, Mexico. The trip was photographed and published in the “Life” magazine with the title “Seeking the Magic Mushrooms”, being a milestone in the dissemination of psychoactive mushrooms to the general public.

After that, a sample of the mushroom was sent to the Swiss chemist Albert Hoffman, who had already discovered the effects of LSD in 1943, a synthetic substance with properties similar to psilocybin. In 1959, Hoffman ingested about 2.4g of the substance, proving its psychedelic effects, in addition to isolating, crystallizing, and naming the compound as psilocybin. The drug was later synthesized and marketed by Sandoz as “Indocybin” [1]. In parallel, research with LSD, a classic psychedelic with some effects similar to the mushroom, had been advancing since its discovery, culminating in the first international conference on the therapeutic uses of LSD [2].

Chronology of Scientific Advances

After these discoveries, many clinical research studies were conducted in the fields of psychology and psychiatry to explore the mystical and introspective effects of psychedelics, mainly LSD, as well as their possible therapeutic applications [2]. A meta-analysis that evaluated 19 studies of psychedelics for mood disorders [3] published between 1949 and 1973 found that 79% of patients showed “clinically judged improvement” after treatment. In 1962, at Harvard University with the support of the pharmaceutical company Sandoz, psychology professor Timothy Leary led several studies, including studies on psilocybin in psychotherapy with guests, artists, religious professionals, and psychology students. These studies were motivated by his psychedelic experience in the Cuavernaca region, which he reported as one of the most remarkable of his life [4]. Additionally, in the following years, several studies were conducted, showing that classic psychedelics, when associated with psychotherapy, generate promising results in patients with psychiatric suffering secondary to cancer and substance dependence [5-7].

In the mentioned context, there was an increase in the non-medical use of psychedelics by young people, associated with the counterculture movement in the United States. This generated a political reaction that significantly limited the continuity of research in this area. In addition, there was a tightening of regulations in pharmaceutical research, causing ongoing research to lose credibility for not meeting the required scientific standards [8]. Until then, there was no convincing evidence on the efficacy and safety of psychedelics for the treatment of clinical conditions, which resulted in the prohibition of pharmaceutical research with these substances. Additionally, for political reasons, in 1970 the United States classified psilocybin, mescaline, and LSD as drugs of abuse, criminalizing their consumption and possession and denying any therapeutic value, mandatory without any scientific basis. Clinical studies with psychedelics practically ceased for more than 20 years until the founding of the Heffter Research Institute in 1993, dedicated to the clinical research of the therapeutic potential of these substances.

This period marked the “New Psychedelic Renaissance”, characterized by research advances, showing few adverse effects and great efficacy when combined with psychotherapy [9]. In this systematic review article, we will conduct a literature review of current clinical trials on the use of Psilocybin in the treatment of mental disorders such as treatment-resistant depression, anxiety, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder, smoking, and alcoholism, with the purpose of presenting consistent or inconsistent findings in the field.

Mechanism of action

Psilocybin is an alkaloid pro-drug derived from tryptamine precursors found in various species of fungi and is classified as a classic psychedelic (serotonin 2A [5-HT2A] receptor agonist) [10], along with LSD, mescaline, and DMT, which have the ability to promote profound alterations of consciousness, modulating emotions, sensory perception, and sense of self [11]. The substance, after administration, undergoes dephosphorylation in vivo and gives rise to psilocin (the active drug), responsible for the psychomimetic effects. The active drug is an agonist not only of 5-HT2A receptors and other serotonergic receptors, but current evidence shows that it also binds allosterically to the TrkB receptor, improving BDNF signaling, responsible for neuroplasticity, whose reduced levels have been associated with depressive symptoms [12]. The 5HT2A receptors are widely distributed in various brain areas, including the frontal, parietal, temporal, and occipital lobes, related to attention, perceptual awareness, thinking, language, and cognitive control. Additionally, the amygdala, a brain region that functions as a sensory connection during the process of emotional learning, also has a high expression of 5HT2A receptors, significantly impacting the creation and retention of emotion-related memories [13].

The cellular neurobiology of psychedelics is still being studied, and a systematic review on the topic [7] showed a variety of molecular, circuit, and overall brain-level mechanisms that are interconnected. The basic mechanism for the others is the molecular one, through the activation of serotonergic receptors, tropomyosin receptor kinase B (TrkB) receptor, and dopamine receptors, promoting the following effects: increased glutamate and oxytocin, production of brain-derived neurotrophic factor (BDNF) that stimulates neurogenesis, neuroplasticity, and leads to increased connectivity between neurons. At the brain level, an increase in the flow of information modulated by sensory signals was observed, associated with cognitive and sensory cortical region changes.

Adverse Effects

An analysis demonstrated that psilocybin has a benign profile [14] being considered low-risk for self-harm and harm to others compared to more common drugs of abuse such as alcohol. A systematic review and meta-analysis examined the acute adverse effects of therapeutic doses of psilocybin [15], observing that these effects generally resolve within 24 to 48 hours. The most common include headache, nausea, anxiety, dizziness, changes in blood pressure and/or heart rate, visual perceptual effects, and physical discomfort.

The most serious adverse effects found in the literature include persistent psychosis, mania, and suicide attempt, especially in case reports [71-74] [16-19] with recreational use of mushrooms, where there was no dose control or psychological support for the experience. The risks increase significantly when psychedelics are mixed with other drugs and/or alcohol [20], which can even result in death. Additionally, there is no record of a withdrawal syndrome associated with the use of psychedelics [21], indicating a low risk of dependence according to current DSM-V diagnostic criteria.

Due to the possibility of psychosis, the use of psilocybin is contraindicated in patients with a personal or family history of schizophrenia, psychosis, bipolar disorder, and borderline personality disorder. It is also a relative contraindication for people with severe or uncontrolled cardiovascular conditions, due to the frequently reported increase in blood pressure and heart rate during the sessions [22]. With appropriate inclusion and exclusion criteria and clinical supervision, adverse physiological reactions are minimal, and this was the case in the clinical trials included in this review.

Therapeutic Effect

Therapeutic doses of psilocybin allow patients to experience positive changes in their lives, such as greater self-knowledge, mood improvement, relationships, spirituality, well-being, and life satisfaction, impacting their behaviors. Studies also point to subjective effects on empathy, creative thinking, ego dissolution, a positive sense of self, and the enhancement of expectations [5,23]. It is often speculated that, after the psychedelic experience, patients acquire “insights” that motivate them to change negative thought patterns, as in depression, or behavior, as in tobacco abuse.

However, the “mind”, “set”, and “setting” aspects significantly influence the effects of the psychedelic experience. The “mind” refers to the emotional state and any pre-existing psychopathology in the individual; the “set” refers to the expectations and attitudes, where an open mindset and positive attitude contribute to a more rewarding experience; and the “setting” refers to the physical and social environment, where a safe and comfortable environment, with soft lighting, appropriate music, and the presence of compassionate guides or therapists, enhances the positive effects of the substance [24]. The combination of these elements is crucial in shaping the nature of the psychedelic experience and its long-term outcomes, highlighting the importance of careful preparation and a supportive environment to maximize therapeutic benefits and minimize possible adverse effects [1].

Thus, Psilocybin-Assisted Psychotherapy (PAP) has been extensively studied as a therapeutic approach that combines the use of psilocybin with psychotherapy techniques, which is structured in three phases - pre-treatment, treatment, and post-treatment - that prepares participants, provides psychological support during the administration of psilocybin in a controlled environment, and helps in the integration of the insights obtained, promoting lasting improvements in mental health through a safe and emotionally supportive environment [1].

Method

The systematic review search was performed in the PubMed electronic database up to December 2023. The MeSH terms used for the search were: “psilocybin AND mental health”, “psilocybin AND psychiatric disorders”, “psilocybin AND PTSD”, “psilocybin AND depression”, “psilocybin AND anxiety”, “psilocybin AND smoking”, “psilocybin AND tobacco”, “psilocybin AND alcohol”, “psilocybin AND addiction”, “psilocybin and compulsive disorder”. We also used the “randomized controlled trial” and “clinical trial” filters to assess the clinical trials, which have greater scientific impact compared to case reports or observational studies, for example. In addition, parallel searches with the “systematic review” and “meta-analysis” filters were performed to strengthen the findings. With the filter for evaluating clinical trials, which is the main objective of this systematic review, a total of 174 articles were identified and superficially analyzed by their titles and abstracts.

To obtain more comprehensive results of relevant clinical findings, we included randomized, open-label or double-blind clinical trials, as long as they were conducted on humans. We excluded duplicates, animal studies, healthy volunteers, recreational use analyses, secondary analyses, microdose studies, studies unrelated to the review topic, and those without full-text access, leaving 33 to be read and evaluated in full. It is worth noting that articles that evaluated recreational use, case report, or retrospective study were relevant in some points, although they were not included in the systematic review. Additionally, one clinical trial was included [58] even without full-text access, compiling information from its abstract and citations in other articles.

The most relevant ones for the chosen scope were reviewed by 2 or 3 authors who discussed and reached a consensus, with the third author being consulted when there was any disagreement. Finally, 18 articles were selected and summarized in a table with the main points (Appendix 2) reporting evidence when investigating the efficacy of psilocybin for the treatment of treatment-resistant depression, anxiety, obsessive-compulsive disorder (OCD), smoking, and alcoholism, which also contributed to its historical scientific elucidation and the neural mechanisms involved. In addition, we also analyzed the risk of bias (Appendix 3) using the Rob2.079 (Revised Cochrane risk-of-bias tool for randomized trials) criteria for all articles, except for the OCD one, given the insufficient information.

Development

Depression

According to the WHO, around 280 million people worldwide suffer from depression, with approximately 700,000 people with depression dying by suicide each year. This disorder is one of the leading global causes of disability, with loss of pleasure or interest in activities and depressed mood, affecting all aspects of the individual’s life [25]. It is assumed that this is related to dysfunctions in the amygdala, particularly its hypersensitivity to negative stimuli, leading to disturbances in emotional processing [26]. This is because the amygdala is a brain area responsible for the formation of emotional memories, making a sensory interface during emotional learning [27], a fact that has made it a target of antidepressant medications26. Despite the availability of pharmacological therapies, the treatment response is limited and with many adverse effects, leading to low patient adherence [27]. A meta-analysis involving 38 studies showed that the average response to conventional treatment is about 27%, that is, only one in 3 patients substantially improve [28]. In this context, in recent years, there has been a significant increase in the search for alternative treatment options, which has been accompanied by a series of studies involving the use of psilocybin and other psychedelics [3,15,29-33].

Some studies show that the vast majority of patients already have an improvement in depressive symptoms within 1 week after the high-dose (25mg) psilocybin session [26,34-38], with the positive effects lasting for 3 [36], 6 [37] and up to 12 months [39] of psilocybin-assisted psychotherapy. The average response rate to treatment is about 69% in 1 week, with complete remission of depressive symptoms of approximately 57% in the same period.

Neuroimaging studies evaluated brain function changes before and one day after psilocybin administration, one of which showed that the changes in brain activity during the acute psychedelic experience are different from those observed one day later. A transient activation of the amygdala was observed, followed by a decrease in its blood flow one day after treatment, which was related to the reduction in depressed mood35,36. In addition, an acute decrease followed by an increase in the integrity of the default mode network, responsible for self-perception, was observed. This process is similar to that observed in a study with depressed patients who responded to electroconvulsive therapy (ECT) [40], which promotes a “brain reset”, offering the patient the opportunity to restructure their mental processes, allowing a new perspective and approach in relation to their thoughts and experiences.

Two additional studies used magnetic resonance imaging to evaluate changes in the amygdala’s response to facial expressions before and after psilocybin sessions. These studies [36,26] revealed that, after treatment, there was a significant increase in the amygdala’s responsiveness to faces expressing fear. This increased emotional reactivity was correlated with reports from most patients about greater acceptance of their own emotions, including negative ones [36], as well as an increase in emotional sensitivity [26]. It was observed that the increase in amygdala activity, along with the reduction in functional connectivity with prefrontal control regions, may be related to a decrease in emotional rumination and an increase in the ability to accept [26]. On the other hand, conventional antidepressants, especially Selective Serotonin Reuptake Inhibitors (SSRIs), tend to reduce amygdala activity, resulting in a decreased emotional responsiveness to both negative and positive stimuli, leading to a sense of emotional numbness [41].

In a comparative study between escitalopram and psilocybin [42], it was found that over a 6-week period, there was no significant difference in changes in depression levels between the groups. However, the response to psilocybin was significantly better and showed faster efficacy compared to escitalopram. Additionally, participants who received psilocybin reported a considerable improvement in their perceived ability to cry and feel compassion, as well as experiencing intense emotions and pleasure. They also reported feeling less sleepy compared to the escitalopram group.

Two recent randomized double-blind clinical trials published in 2023 [39,43] - one involving 233 individuals suffering from treatment-resistant depression and another with 104 participants meeting DSM-5 criteria for major depressive disorder - provided new evidence on the immediate beneficial effects of a single dose of psilocybin. The results highlighted its remarkable efficacy, when combined with psychotherapy, in reducing depressive symptoms, improving anxiety levels, increasing positive feelings, as well as enhancing functionality and quality of life in these patients.

In this context, psilocybin and other psychedelic substances are the only known agents that show a positive correlation between a temporary mechanism of brain reset and antidepressant response. This finding has the potential to revolutionize the treatment of depression after ECT, opening new perspectives and possibilities in the field of mental health [41].

Anxiety

Anxiety is the most common mental disorder in the world, affecting over 370 million people, according to the WHO mental health report [25]. In fact, patients with a highly lethal disease often suffer considerable anxiety, discouragement, indignation, personal devaluation, social withdrawal, lack of hope, and vulnerability [45]. The attribute of lethality of cancer and the uncertainty related to its evolution can cause considerable psychological turmoil, with the fear of cancer recurrence and death also contributing to anxiety [30]. This leads to insufficient recovery from medical interventions and lower life expectancy in terminal patients [45]. Even though psychopharmacological and psychosocial interventions are used in the approach to anxiety in patients with life-threatening illnesses, the effect is limited, leading to an analysis of the effectiveness of psilocybin in these cases through clinical trials [30].

The clinical trials show that, even at a low dose, psilocybin reduced anxiety levels at 1 and 3 months post-treatment, reflecting a reduction in stress [46], significantly increased spiritual well-being [7], mood, quality of life, and improved perspective and anxiety regarding death [5,7]. Furthermore, a double-blind randomized clinical trial involving 51 cancer patients showed an 83% clinical response rate assessed in relation to anxiety after 6 months [5], significantly reflecting their satisfaction with life. Such repercussions were closely linked to the mystical experience promoted by psilocybin, which includes commonly reported reflections on insights and new perspectives, evaluating the disease and death differently, with greater acceptance [46].

The analyzed studies indicate that a careful application of psilocybin combined with psychotherapy manifests itself as a possible revolutionary pharmacological-psychosocial therapy to manage the psychological and existential suffering linked to cancer. However, the evidence is still insufficient, and more clinical trials are needed to reach a more consistent conclusion.

Post-Traumatic Stress Disorder (PTSD)

Post-Traumatic Stress Disorder (PTSD) involves distressing symptoms such as persistent psychological distress, mood changes, dissociative reactions, and avoidance of trauma-related stimuli. This can occur after exposure to a traumatic event, such as serious injury, sexual violence, or death [47]. The pathophysiology of PTSD is still being studied, but it is mainly related to functional changes in neural connectivity, such as hyperexcitation of the amygdala to traumatic events, leading to a dysregulated fear response, and hypoactivation of the default mode network, associated with symptoms of avoidance, dissociation, and intrusive thoughts [48]. The first-line treatment for this disorder is exposure-based psychotherapy, however, 40-60% of patients do not respond adequately to this treatment and suffer from chronic effects [49].

Additionally, the difficulty of patients in tolerating the re-experiencing of traumatic memories can impair the treatment response and lead to dropout [50]. In view of this, some research has aimed to explore the psychedelic effects associated with psychotherapy, seeking to increase the cognitive and emotional processing capacity through pharmacological reduction of fear and arousal [51]. Before the introduction of PTSD as a psychiatric diagnosis in the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM) in the 1980s, hundreds of patients in the Netherlands with the so-called concentration camp syndrome were treated with psilocybin by psychiatrist Jan Bastiaans, with the idea of re-living the traumatic event with emotional abbreviation associated with psychological support. This method was used by Ossebaard and Maalsté in 1999 in a long-term study involving 12 traumatized participants, in which all except 1 reported moderate to strong improvements [51].

Among the current studies with psychedelics, no completed clinical trials involving psilocybin in the treatment of this disorder were found, only with MDMA [31] and ketamine [32,33], which are currently more explored as alternative therapy for PTSD. Despite this, there is great potential for psilocybin in the treatment of PTSD, through the reduction of fear response. In this way, its association with psychotherapy could facilitate trauma exposure, by decreasing the negative reaction that the patient may have during the session, along with acute effects of greater understanding and acceptance [35]. However, the research gap does not sufficiently demonstrate whether psilocybin is useful in the treatment of PTSD.

Obsessive-Compulsive Disorder (OCD)

Obsessive-Compulsive Disorder (OCD) manifests through obsessions and/or compulsions that are not attributed to substance use or physical disturbances, which results in personal distress and dysfunction, through a chronic or episodic course. Obsessions consist of recurrent thoughts that cause anxiety, while compulsions are repetitive actions performed in response to these thoughts or according to specific rules, with the aim of relieving distress [52]. We still do not fully understand the physiology of this disorder, however, some theories point to a possible influence of dysfunction in the cortico-striato-thalamo-cortical circuits, which are closely related to sensory-motor, cognitive, affective, and motivational processes. Furthermore, it is speculated that imbalances, particularly in the functioning of the main neurotransmitter systems, such as dopamine, GABA, and, especially, serotonin and glutamate, may also be associated with this condition [39]. Thus, the first-line treatment is cognitive-behavioral therapy (CBT) and pharmacological intervention with a selective serotonin reuptake inhibitor (SSRI), however, between 40-60% of patients suffer from therapeutic response failure and relapses after discontinuation or completion of these treatments. In more severe and refractory cases, neurosurgical procedures focused on the lesion of specific components of the neural circuits implicated in OCD may be indicated [53]. Thus, it is extremely important to explore other treatment alternatives for refractory cases, in a minimally invasive manner and with greater efficacy.

A variety of case reports were found in the literature on the effects of psilocybin in patients with OCD [54-56], highlighting remarkable improvements in obsessive thought patterns and compulsive behaviors after the experience. However, the vast majority occurred in a recreational manner, without any clinical control, making it impossible to relate dose, effect, and duration of the therapeutic effect. Among them, a retrospective online study published in September 2023 [57] explored the recreational use of psychedelics and the improvement of OCD symptoms, evaluating changes in negative emotions, obsessions, compulsions, acceptance of the condition, and avoidance of anxiety-provoking situations. It was concluded that among the psychedelic users (90 participants), 42% reported that the use of psilocybin had a significant impact on symptom reduction, with more than 30% reporting persistence of effects for more than 3 months, and 10% reporting a worsening of OCD symptoms. However, no significant predictors were identified that could explain the variation in participant reports.

In addition, a single double-blind clinical trial conducted in 2006 was found [58], evaluating the safety, tolerability, and potential therapeutic effects of psilocybin in OCD with 9 individuals who had failed previous treatment. In this study, the participants received oral doses of psilocybin combined with unstructured psychological support, once a week, for 4 weeks. The results showed a significant reduction in OCD symptoms, with decreases of 23 to 100% in Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores 24 hours after dosing. No serious adverse events were observed, and one participant maintained complete remission of symptoms at the 6-month follow-up. It is noted that the evidence is insufficient to affirm anything regarding the efficacy of psilocybin in the treatment of OCD, despite its potential in facilitating the reprocessing of negative emotions and core beliefs associated with aversive past events, in order to allow behavioral changes.

Smoking

Smoking is a chronic disease caused mainly by nicotine dependence present in cigarettes. Nicotine is a highly addictive substance that acts on nicotinic receptors present in the central nervous system, activating the brain’s reward system and increasing the release of dopamine, a neurotransmitter related to pleasure and well-being. This mechanism causes the compulsive use of cigarettes, even in the face of health harms [59]. Smoking is one of the leading preventable causes of death worldwide, being associated with a variety of diseases such as cancer, cardiovascular, and respiratory diseases [60].

Although there are various treatment options to aid in smoking cessation, which includes behavioral interventions through psychotherapy [20] and pharmacological treatments such as nicotine replacement therapy and medications like bupropion and varenicline, the success rates are still relatively low61. It is estimated that about 70% of smokers who try to quit without medical assistance relapse within a month. With conventional treatments, success rates range from 20% to 30% after one year of treatment, which shows that there is still room for the development of more effective therapies [62]. Some mechanisms of action are defended to justify the therapeutic use of psilocybin, such as the effect on the serotonergic system activity, which modulates the reward-seeking behavior, and the ability to increase brain neuroplasticity, reducing stress response and improving the individual’s cognitive ability to resist the temptation to smoke [63,64].

In a pilot study conducted at Johns Hopkins University [63] with psychiatrically healthy nicotine-dependent patients, 80% of participants showed tobacco abstinence over 10 weeks of treatment with psilocybin combined with cognitive-behavioral therapy for smoking cessation, which persisted at the 6-month follow-up. Additionally, participants frequently reported that the experience strengthened their belief in their ability to quit smoking and changed their perspective on the situation, so that the long-term benefits outweighed the immediate pleasure of smoking. The long-term follow-up of this same study [65] showed that the abstinence level after more than 1 year of the psychedelic experience was 60%. A systematic review on the topic [29] strengthens the evidence found here, allowing to elucidate that high doses of psilocybin in association with cognitive-behavioral therapy and counseling for smoking cessation favor tobacco abstinence.

Therefore, psychedelic therapy can be a promising therapeutic option for the treatment of tobacco dependence. The results suggest that such therapy can lead to profound changes in patients’ perception and behavior towards smoking, which may result in a significant reduction in dependence and tobacco abuse. However, controlled clinical trials are needed to evaluate the efficacy and safety of psychedelic therapy in the treatment of tobacco dependence.

Alcoholism

Alcoholism, also known as alcohol use disorder, is a chronic disease characterized by the excessive and uncontrolled use of alcoholic beverages, negatively affecting various aspects of the individual’s life. The mechanism of alcohol addiction is related to the activation of the brain’s reward system, which releases dopamine in response to alcohol consumption, generating a sense of pleasure and well-being [66]. Over time, the continuous use of alcohol can lead to a reduction in the sensitivity of dopamine receptors, causing the individual to need increasingly higher doses to achieve the same pleasurable sensation. In addition, alcohol can affect other brain systems, such as the GABA and glutamate neurotransmitter systems, which are involved in mood regulation, anxiety, and sleep, contributing to the disorder [67].

The conventional treatment of alcoholism aims to reduce alcohol consumption and prevent relapse. Treatment options include psychotherapy, participation in support groups, and the use of medications such as naltrexone and acamprosate [68]. Although there are some treatment options, the success rate is still low. It is estimated that only about 10% of people suffering from alcoholism are able to fully recover [32] and > 65% experience relapse within 12 months after treatment [29]. Given this, alternative treatment with psilocybin seems to be a good option, as it acts on the serotonergic system, modulating the reward-seeking behavior and increasing brain neuroplasticity. This can help reduce the brain’s stress response and enhance the individual’s ability to resist the temptation to drink [13].

A 2016 pilot study with 10 participants investigated the use of psilocybin in the treatment of alcoholism and showed promising results: a significant reduction in the frequency of drinking days and the amount of alcohol consumed, as well as a relationship between the intensity of the psychedelic experience and the change in drinking behavior, desire, and self-efficacy in most participants [69]. In addition, in 2022, a larger randomized clinical trial [70] was published involving 95 participants with alcohol use disorder who were divided into 2 groups: 49 for psilocybin and 46 for the active placebo control diphenhydramine, in order to evaluate improvement in alcohol consumption associated with psilocybin-assisted psychotherapy. A significant reduction in the percentage of heavy drinking days was observed in patients treated with psilocybin (9.7%) compared to the active placebo (23.6%), in addition to a moderate to large reduction in various categories of alcohol-related problems that persisted after 24 and/or 36 weeks after the first medication session.

In summary, regarding the application of psilocybin in substance use disorder, the impact of the mystical-type experience on the lasting effect of psilocybin was addressed, since it induces behavioral change in the individual, facilitating the reduction in the compulsivity to drink, with positive and lasting effects [29]. Despite these promising results, the evidence is scarce, and more randomized double-blind placebo-controlled clinical trials are still needed to evaluate the efficacy and safety of using psilocybin in the treatment of alcoholism.

Discussion

It is observed that there is currently a deeper exploration in clinical research on the therapeutic effects of psilocybin in the treatment of mental disorders. This systematic review analyzed 18 clinical trials in humans that evaluated the application of psilocybin-assisted psychotherapy in treatment-resistant depression and anxiety primarily, and to a lesser extent in smoking and alcoholism. As for OCD and PTSD, the studies are scarce and limited to a few case reports or very old studies, with only one clinical trial found in OCD.

In the field of depression, more research was conducted, with 10 clinical trials identified, 5 of them open [26,34-37] and 5 randomized [42,43,38,39,71], including a recent larger double-blind study published in 202371, which included 233 participants with treatment-resistant depression. The analysis of these studies revealed a significant improvement in depressive symptoms as early as the first week, with sustained effects over periods that extended up to 12 months, suggesting that psilocybin, combined with psychotherapy, is a promising option for treating unipolar depression resistant to conventional treatments.

It is notable that the effects of psilocybin are different in the acute, subacute, and long-term phases, as evaluated by studies that reached different results. During the acute phase, characterized in general by a period of 6 to 8 hours, with the peak of effect occurring between the second and third hour [34], an interaction of the substance with several receptors, with emphasis on the serotonergic ones, is pointed out. This process induces a hyperactivation of the amygdala, a reduction in connectivity in the default mode network, and an improvement in the connection between different brain networks, resulting in the hallucinogenic effects associated with a transient increase in anxiety, possible intrusive thoughts, and a deeper reflection on one’s own life. In the subacute phase, which covers the period from the day after the experience to approximately one month after, some studies using brain imaging methods pointed to a decrease in blood flow in the amygdala, correlating with the reduction of depressive symptoms, in addition to an increase in the integrity of the default mode network, associated with self-perception [35].

Additionally, some of the studies indicated increased amygdala sensitivity to fear stimuli [36,26] and reduced functional connectivity between the prefrontal cortex and the amygdala, which was associated with a decrease in emotional rumination due to greater acceptance of their emotions. The fact that there is an increase in the integrity of the default mode network (after an acute decrease) accompanied by mood improvement was the basis for the comparison of the psychedelic experience with electroconvulsive therapy [35], in which an acute modular disintegration allows a reintegration and resumption of normal functioning, like a “brain reset”, resulting in behavioral and cognitive changes, in addition to providing insights into life. This period after the experience, called the “psychedelic afterglow”, opens a therapeutic window that enhances the beneficial effects of psychotherapy, allowing an extension of these benefits over time. Thus, after one week of treatment, on average, 67% of the evaluated patients showed a significant reduction in negative thoughts, a broader perception of the situation, and a greater capacity for acceptance [5,36,26].

The significant improvement in depressive symptoms observed in the evaluated clinical trials represents a revolutionary advance in psychiatry. This is particularly relevant considering that conventional antidepressant treatments, such as selective serotonin reuptake inhibitors (SSRIs), generally require weeks to months of daily consumption to produce significant effects, associated with side effects such as emotional numbness, drowsiness, weight gain, and increased risk of suicidal ideation. Additionally, about 1 in 3 patients do not respond adequately to treatment [72]. In contrast, it was observed that one or two doses of psilocybin produce rapid and lasting effects by addressing central psychological issues through profound and transformative experiences, with fewer side effects and at least comparable efficacy to SSRIs, as evidenced by a comparative study with escitalopram [42].

Regarding anxiety, three double-blind randomized clinical trials were identified that investigated the therapeutic potential of psilocybin in reducing end-of-life anxiety in cancer patients [5,7,46]. These patients often experience a chronic syndrome of psychosocial distress, characterized by depressed mood, anxiety, and deterioration in quality of life. The largest randomized clinical trial included 51 patients diagnosed with potentially fatal cancer. In the three trials found, a significant improvement in quality of life, a decrease in anxiety related to death, and a change in perspective regarding their condition were observed, with participants demonstrating greater acceptance and reflection on their limited life expectancy.

In the context of smoking, two studies were identified [63,65] from the same population data, although with distinct follow-up periods: an open-label pilot clinical trial was followed by a long-term evaluation of 15 smokers who received psilocybin treatment. The results were encouraging, and approximately 70% of participants reported that psilocybin made them reconsider their habits, valuing long-term benefits over immediate pleasure, and reevaluating their priorities and life values. Regarding alcoholism, two clinical trials were identified, one open [69] and a more recent randomized, double-blind, placebo-controlled [70] trial, which involved 93 participants. These studies showed a reduction in the frequency of heavy drinking episodes, with effects persisting for up to eight months in patients undergoing psilocybin sessions.

Regarding Obsessive-Compulsive Disorder (OCD), only one clinical trial [71] conducted in 2006 was found, but we did not have access to the full text and made an exception to the exclusion criteria, given the relevant information found in other review articles. In this sole study, nine individuals were included and showed significant reductions in obsessive-compulsive symptoms even with the administration of low doses of psilocybin, suggesting a possible influence of the placebo effect. In addition, there are only a few isolated case reports that, despite demonstrating frequent changes in thought patterns and behavior, provide limited evidence. The same scenario applies to Post-Traumatic Stress Disorder (PTSD), for which no clinical trials with psilocybin meeting our inclusion criteria were found, despite the promising possibilities and preliminary studies conducted in the past. Considering the impact of psilocybin on the amygdala, it is plausible that this substance may be effective in the treatment of PTSD, allowing patients to address their traumas openly and with greater acceptance, which may facilitate psychotherapy. However, its efficacy cannot be affirmed.

Regarding the adverse effects reported in the evaluated studies, the majority were of a transient nature, including mainly increases in blood pressure, heart rate, headache, and nausea. In terms of psychiatric adverse effects, transient symptoms of anxiety, transient psychotic symptoms, and a single case of passive suicidal ideation [72] that lasted approximately 15 minutes during a session were reported. No persistent psychotic disturbances or hallucinations were reported. Given this, it is emphasized that the immediate effects of psilocybin are influenced by various factors, including the environmental context of the experience, the user’s expectations, and their emotional processes [73. In inadequate circumstances, the recreational use of the substance can lead to rare cases of psychological harm, as reported in some cases associated with the use of psychedelics [74-78]. Therefore, all clinical trials conducted in this research carefully considered the context of psilocybin administration. This included the psychological preparation of participants through pre-experience therapy sessions, which addressed aspects of the participants’ personal life, the expected psychological effects of psilocybin, guidance for openness to new perceptual possibilities, and the establishment of bonds with the therapists. During the experience, the participants received psychological support to minimize harm, control possible challenging experiences (“bad-trips”), and promote the acceptance of images, visions, and perceptions. Additionally, the environment where the sessions took place was carefully prepared to be comfortable and quiet, with soft lighting and selected music to complement the therapeutic experience.

The significant role of music in this context is also highlighted, as it plays a crucial role in guiding and improving the therapeutic experience, assisting in the processes of meaning attribution, emotional regulation, and the creation of mental images. This probably occurs due to the fact that the brain regions involved in the auditory processing of music overlap, in part, with the brain areas whose activity is altered after the administration of psychedelics [79]. Therefore, the appropriate context acts in synergy with the pharmacology of psychedelics to promote the desired therapeutic effect. In this circumstance, the significant role of the mystical experience was also observed in many of the analyzed studies [5,7,69,29,34,39,46], positively influencing the results. It is suggested that this experience may provide frequent insights, expanding personal perception through neuroplasticity, which allows the restructuring of ideas and behaviors. In the long term, participants consistently reported an amplification of positive effects, including feelings of gratitude, well-being, life satisfaction, humility, motivation, mindfulness, and openness to new experiences.

Although these studies present promising results, they face significant bias challenges, as highlighted in a recent systematic review on the risk of bias in psychedelic medicine [80]. It is common to have bias in deviations from intended interventions, as the effective blinding of participants is complicated due to the strong effects of psilocybin, which often reveals who received placebo and who received the active compound, impairing the ability to control factors that may affect treatment efficacy, such as patient expectations and the quality of the therapeutic relationship. Additionally, most trials have small samples, which do not adequately reflect the real effect of the treatment and limit the representativeness of the target population, restricting the generalization of the results.

It is important to note that the study participants are predominantly of white ethnicity, with high educational level, and belong to social groups that include little representation of LGBTQ+ people or other marginalized populations. This lack of diversity is concerning, as different groups may react differently to treatments, influenced by genetic, cultural, and socioeconomic factors, in addition to having various perspectives and resources to address mental health issues. The absence of diversity may limit the applicability of the results to a wider range of populations. Furthermore, there is no standard methodological protocol, resulting in variations in the administered doses, which makes comparative analysis difficult. Finally, the studies present considerable selection bias due to rigorous exclusion criteria, which reduces clinical applicability, especially by excluding patients with comorbidities such as psychotic disorders, borderline personality disorder, and bipolar disorder, thus limiting the usefulness of psychedelics in the real-world context.

This systematic review has significant limitations. First, the search was conducted in a single database, PubMed, which may restrict the breadth of the results. Additionally, the lack of access to articles considered relevant [81-84] due to payment restrictions compromises the inclusion of important information (except for one, which we found relevant to include as much as possible, also being a limitation). The evaluated studies also have characteristics that limit the robustness of the findings, such as the conduct of open-label trials, the use of small and homogeneous samples, and concerns about bias. Furthermore, the dependence on funded research and the publication bias associated with the current psychedelic renaissance may distort the available evidence. Finally, the speed with which new discoveries are disseminated can quickly make this review obsolete, requiring constant updating of the information.

Conclusion

The systematic review on the use of psilocybin in the treatment of mental disorders indicates promising results. The analyzed clinical trials suggest that, when administered in controlled environments and combined with psychotherapy, psilocybin can provide significant improvements in patients with treatment-resistant unipolar depression, end-of-life anxiety, as well as problems related to alcoholism and smoking. Although only one clinical trial was found for obsessive-compulsive disorder (OCD) and none for post-traumatic stress disorder (PTSD), the potential of psilocybin to alleviate the symptoms of these disorders is evident, as it acts on brain mechanisms that influence the fear response and promote changes in thought and behavior patterns.

The studies demonstrate a significant reduction in depressive and anxiety symptoms, with therapeutic effects that manifest quickly and are maintained over time, resulting in improvements in quality of life and well-being of patients. This contrasts with conventional treatments, which often take longer to show results and are frequently associated with adverse effects. In contrast, the side effects of psilocybin tend to be temporary and manageable in appropriate therapeutic contexts, highlighting the importance of careful psychological preparation and a conducive environment to maximize the benefits of the psychedelic experience. Additionally, elements such as music and mystical experiences are fundamental to the effectiveness of the treatment. In summary, psilocybin stands out as a promising alternative in the treatment of mental disorders, presenting a profile of efficacy and safety that justifies the need for additional investigations to validate its clinical applications.