Introduction
The need for new treatments for psychiatric disorders is evidenced by increased research into novel pharmacological approaches.Reference Cole, Phillips and Bentzley 1 -Reference Serretti 3 Standard antidepressant drugs are widely used in depressive disorders but not without drawbacks. These include high nonresponse rates, the persistence of some residual symptoms (e.g., cognitive and sleep disturbances), undesirable metabolic and sexual side effects,Reference Serretti and Chiesa 4 -Reference Sforzini, Worrell and Kose 7 as well as the delayed onset of therapeutic effects.Reference Scala, Fanelli, De Ronchi, Serretti and Fabbri 8 Antidepressants are also used to treat other psychiatric disorders including obsessive-compulsive disorder (OCD),Reference Del Casale, Sorice and Padovano 9 post-traumatic stress disorder (PTSD),Reference Akiki and Abdallah 10 and substance use disorder (SUD).Reference Iqbal, Levin and Levin 11 However, despite the establishment of an appropriate treatment paradigm with current antidepressants, up to 60% of patients with OCD continue to experience debilitating residual symptoms,Reference Del Casale, Sorice and Padovano 9 and less than 30% of patients with PTSD achieve clinical remission.Reference Akiki and Abdallah 10 Standard antidepressants produce inconsistent improvements when treating depression associated with SUD.Reference Iqbal, Levin and Levin 11 These challenges highlight the need for novel, rapid-acting pharmacological approaches to possibly overcome the limitations of standard antidepressants.
Within this context, psychedelics have received much attention over the past few years. Although researchers started to explore the effects of psychedelics in the 1950s,Reference Meyer, Meir, Lex and Soares 12 psilocybin only recently was granted the status of breakthrough therapy by the Food and Drug Administration (FDA) for treatment-resistant depression (TRD).Reference Rahhal 13 The latter was not an endorsement for clinical use, but an invitation to provide further evidence on which clinical decisions can be based. The principal reason for this caution can be identified in previous trials’ methodological issues that have contributed to classifying psilocybin as a drug of abuse with no medical value over the past 50 years.Reference Phelps 14 Furthermore, the psychoactive effects of psilocybin, including disturbances of consciousness, mood, perception, and thought, left this drug for recreational use rather than a potential psychopharmacological treatment.Reference Dodd, Norman and Eyre 15 Indeed, the historical primary use of psilocybin in ancient indigenous rituals intended to induce mystical experiences and a simultaneous altered state of consciousness, thus allowing for better processing of unconscious memories.Reference Griffiths, Richards, McCann and Jesse 16
More recently, these effects were found to be closely dependent on plasma psilocin levels (i.e., psilocybin’s active metabolite) and serotonin 5HT2A receptor occupancy rates,Reference Madsen, Fisher and Burmester 17 which increases glutamate tone, thus leading to more active synaptic plasticity.Reference Jakab and Goldman-Rakic 18 Despite these compelling pharmacodynamic properties, a 2016 survey revealed conflicting opinions among clinicians regarding the possible use of psilocybin for therapeutic purposes. Only 43% of the participants expressed support, while the majority of responders perceived the use of hallucinogens as potentially hazardous.Reference Barnett, Siu and Pope 19
However, recent brain imaging studies aimed at elucidating psilocybin’s therapeutic mechanisms showed significant changes in brain connectivity.Reference Wall, Harding, Zafar, Rabiner, Nutt and Erritzoe 20 , Reference Preller, Duerler and Burt 21 Functional magnetic resonance imaging (fMRI) and perfusion studies conducted before and after treatment showed decreased activation and reduced cerebral blood flow in the amygdala,Reference Carhart-Harris, Erritzoe and Williams 22 as well as variations in prefrontal-limbic functional connectivity.Reference Mertens, Wall, Roseman, Demetriou, Nutt and Carhart-Harris 23 , Reference Gill, Puramat and Patel 24 Psilocybin also decreases brain modularity, correlating with clinical outcomes, unlike the selective serotonin reuptake inhibitor (SSRI) escitalopram.Reference Carhart-Harris, Bolstridge and Rucker 25 , Reference Carhart-Harris, Giribaldi and Watts 26 Electrophysiology studies also revealed that psilocybin reduces alpha, beta, and delta band activity in both healthy and depressed individuals, while an increase in theta power correlates with depressive symptoms improvement in major depressive disorder (MDD).Reference Le, Wong and Badulescu 27 , Reference Skosnik, Sloshower and Safi-Aghdam 28
Preliminary literature provides converging evidence about the potential therapeutic efficacy of psilocybin after one or two administrations, particularly in mood disorders.Reference Haikazian, Chen-Li and Johnson 29 Psilocybin might also represent a treatment alternative for depression and anxiety comorbid with life-threatening cancers – conditions often resistant to other psychopharmacological therapies –Reference Grassi, Caruso, Hammelef, Nanni and Riba 30 as demonstrated in some randomized, crossover trials, despite their small sample sizes.Reference Grob, Danforth and Chopra 31 -Reference Ross, Bossis and Guss 33 However, these clinical trials showed several limitations that require careful consideration when drawing conclusions about efficacy. Moreover, only one randomized clinical trial (RCT) directly compared the efficacy of psilocybin with escitalopram without demonstrating a significant difference between the two.Reference Carhart-Harris, Giribaldi and Watts 26
After these preliminary findings, Australia has recently become the first country in the world to approve psilocybin for the treatment of TRD, albeit with stringent regulatory oversight requiring ethics committee approval for use in each patient.Reference Nogrady 34 Despite these advancements and the ensuing enthusiasm, psilocybin has not been approved for the treatment of depression or other mental disorders (i.e., anxiety disorders, OCD, PTSD, and SUD) in other countries, and its use in real-world clinical settings will have to face several unresolved issues, which have not been frequently discussed in the literature.Reference Bienemann, Ruschel, Campos, Negreiros and Mograbi 35 -Reference Rossi, Hallak, Bouso Saiz and Dos Santos 37
The present critical review aims to offer an evidence-informed clinical opinion on the possible implementation of psilocybin-based treatment strategies in psychiatric clinical settings, examining the shortcomings of previous studies that assessed the clinical efficacy of psilocybin, as well as discussing the possible obstacles to its use in real-world psychiatric practice. Some suggestions for the potential use of psilocybin in clinical practice will also be made, with particular attention to feasibility and acceptability. The psilocybin’s unique strengths and innovative potential will also be discussed.
Materials and methods
An electronic literature search was conducted using PubMed/MEDLINE for English-language articles published from inception to December 2023. We used the keyword “psilocybin” combined with terms related to depressive disorders, bipolar depression, anxiety disorders, OCD, PTSD, and SUD.
This critical review does not intend to systematically summarize the extent of the effect of psilocybin, given the number of reviews already available in the literature,Reference Haikazian, Chen-Li and Johnson 29 , Reference Watford and Masood 38 but rather to offer an expert clinical opinion on the available evidence and possible future perspectives. Key aspects evaluated include its safety profile, addictive potential, optimal dosing, and the altered states of consciousness that may arise during psychedelic-induced mystical experiences. Moreover, this review evaluates the uncertainty about the efficacy of psilocybin independent of concomitant psychotherapy, as well as the positioning of psilocybin-based therapy within treatment paradigms, its comparative efficacy versus standard antidepressants, the appropriate infrastructure and personnel expertise for its safe and effective implementation, and ethical and legal challenges related to psilocybin use.
Results
Barriers to clinical implementation of psilocybin-based treatments, along with psilocybin’s potential strengths and innovations, are presented in Table 1 and described in the following paragraphs.
Evidence-based strengths and challenges of potential use of psilocybin in real-world clinical practice
Abbreviations: AE, adverse event; HPPD, hallucinogen persisting perception disorder; PAP, psychedelic-assisted psychotherapy; RCT, randomized clinical trial; TAU, treatment as usual.
Safety profile and addictive potential
In evaluating the incorporation of psilocybin into clinical psychiatric practice, a thorough assessment of its safety profile and addictive potential is imperative. In this section, we present the safety warnings related to psilocybin use, providing an opinion on the risk of adverse events when psilocybin is administered in controlled settings.
Overall, the compound was well tolerated in most clinical trials.Reference Scala, Fanelli, De Ronchi, Serretti and Fabbri 8 The most common adverse events include nausea, headache, and minimal reductions in cardiovascular parameters (such as basal heart rate and blood pressure), with frequencies up to 33%, 67%, and 76%, respectively, according to the available trials.Reference Scala, Fanelli, De Ronchi, Serretti and Fabbri 8 A mild activation syndrome characterized by moderate anxiety or fear, tremors, and emotional liability affects between 17 and 23.2% of participants at the beginning of the treatment.Reference Scala, Fanelli, De Ronchi, Serretti and Fabbri 8 When this syndrome is accompanied by transient paranoid ideation, it is colloquially referred to as a “bad trip”. Anxiety, mainly due to psychological discomfort during psychedelic-assisted psychotherapy (PAP), is generally acute and transient and improves with therapists’ reassurance.Reference Anderson, Danforth and Daroff 39 Rates of fatigue and insomnia were found to be above 5%.Reference Scala, Fanelli, De Ronchi, Serretti and Fabbri 8 A major concern is related to the risk of developing hallucinogen-persisting perception disorder (HPPD), which includes two major subtypes. HPPD I, also known as “benign flashback” or “flashback type”, has a short-term, reversible, and benign course.Reference Martinotti, Santacroce and Pettorruso 40 In a study involving a small sample of male patients with AIDS, one participant experienced a post-traumatic stress flashback of a sexual assault two days after the PAP, which may be attributed to HPPD I.Reference Anderson, Danforth and Daroff 39 HPPD II, conversely, usually presents as recurrent, long-term, distressing, and pervasive perceptive disturbances. It’s noteworthy that the Diagnostic and Statistical Manual of Mental Disorders (DSM) does not differentiate between HPPD I and II, and the issue is still controversial.Reference Martinotti, Santacroce and Pettorruso 40 The common symptomatology across both types of HPPD includes recurring visual hallucinations (e.g., flashes and intensified color perception, palinopsia, micropsia, and macropsia), false perceptions of movement, recurrent synesthesia, dissociation, auras, depersonalization, and derealization.Reference Dodd, Norman and Eyre 15 HPPD has mainly been associated with the use of lysergic acid diethylamide (LSD).Reference Martinotti, Santacroce and Pettorruso 40 However, it has also been reported after recreational psilocybin use, often together with alcohol and cannabis consumption.Reference Dodd, Norman and Eyre 15 Despite the limited occurrence of HPPD in clinical studies with therapeutic dosages of psilocybin (10–25 mg), further controlled trials should better explore the clinical implications. It is essential to understand whether the potential occurrence of these transient or enduring psychotic symptoms may represent an obstacle to the therapeutic use of psilocybin.
Regarding possible serotonin toxicity, psilocybin shows a lower risk compared to other psychedelics.Reference Malcolm and Thomas 41 Both psychedelic effects and serotonin syndrome are associated with an increase in 5-HT2A neurotransmissionReference Boyer and Shannon 42 , Reference Thomas, Malcolm and Lastra 43 that is responsible for transient serotonin-related symptoms such as nausea, anxiety, hypertension, tachycardia, visual deficits, motor incoordination, and mild tremors, even at therapeutic doses. These symptoms usually subside within a few hours and typically do not need hospitalization.Reference Honyiglo, Franchi and Cartiser 44 However, there is a tipping point at which 5-HT2A receptor stimulation can occasionally lead to severe intoxications, marked by symptoms such as myoclonus, rigidity, severe hyperthermia, and impaired mental status persisting beyond the psilocybin sessions. In such cases, serotonin syndrome should be considered.
Overall, all the mentioned adverse events display a dose-dependent relationship and can cause significant impairment when combined with alcohol or other psychedelics during recreational use.
Despite the potential for adverse effects, clinical findings remain encouraging. During trials, participants do not express a desire for further PAP sessions or dose increases. Hence, despite psilocybin being classified as a drug of abuse, the US Drug Enforcement Administration (DEA) does not include it among the drugs that can cause dependence and/or addiction.Reference Johnson, Griffiths, Hendricks and Henningfield 45 Based on the evidence so far, a high risk of physical addiction could be excluded. At most, in uncontrolled settings, there is a potential for behavioral dependence, where dopamine release would not be triggered by the drug itself but by an external factor (i.e., the state of mind or the gesture of assumption).Reference Zou, Wang, Uquillas, Wang, Ding and Chen 46
A potential limitation of psilocybin use in clinical settings is the lack of a specific antagonist medication to counteract adverse experiences. Benzodiazepines could be a viable solution in case of mild activation or occasional insomnia after PAP, while low doses of typical (i.e., haloperidol, perphenazine, or sulpiride) or atypical antipsychotics (i.e., aripiprazole)Reference Martinotti, Santacroce and Pettorruso 40 may be used if transient psychotic symptoms occur.
In summary, patients treated with psilocybin generally experience mild and transient side effects, which can be partially alleviated through psychological support provided during PAP. Long-term side effects cannot be well quantified and evaluated at present, given the current lack of well-powered studies. Therefore, we suggest carefully considering the safety profile of psilocybin, but also balancing the risks with the pros; for example, in medical and research settings there is no risk of withdrawal symptoms for psilocybin, and the drug has a sexually and metabolically safe profile.Reference Scala, Fanelli, De Ronchi, Serretti and Fabbri 8 However, further research is needed to understand the safety profile of psilocybin in naturalistic contexts.
Dosing
Establishing a safe and effective dose is fundamental for the medical use of psilocybin. Whether higher dosing or micro-dosing has a better therapeutic effect remains controversial, and the dose–response relationship of psilocybin is still a debated issue. According to two recent dose–response meta-analyses, the most effective dose for depressive disorders appears to be between 24.68 mg/70 kgReference Perez, Langlest and Mallet 47 and 35 mg/70 kg.Reference Li, Hu, Chen and Zhang 48 For TRD, the optimal dose is suggested to be higher, with an effective dose of 40 mg/70 kg, whereas for anxiety lower doses should be considered 22.78 mg/70 kg.Reference Perez, Langlest and Mallet 47 However, these results were likely influenced by publication and reporting bias. While higher dosages may be more effective in some groups of patients, such as those with alcohol use disorders, they may be responsible for more frequent adverse events such as dysphoria and anxiety, particularly troublesome for patients with advanced cancer.Reference Bender and Hellerstein 49 Multi-arms studies testing psilocybin across various psychiatric conditions could help to address this issue.
We suggest here some aspects that researchers and clinicians should consider when tailoring psilocybin dose in clinical settings. First, micro-dosing sessions should be considered before prescribing a macro-dose, considering the patient’s expected sensitivity to adverse events. Second, measuring plasma psilocin levels, as is done with current antidepressants,Reference Cellini, De Donatis and Zernig 50 may help optimize the dose.Reference Madsen, Fisher and Burmester 17 However, it remains to be clarified whether administering another antidepressant in combination therapy influences therapeutic response, regardless of psilocybin’s blood levels.Reference Sarparast, Thomas, Malcolm and Stauffer 51 Lastly, assessing patients’ genetic polymorphisms in psilocybin pharmacodynamic targets might help to predict response.Reference Schmitz, Jain, Slocum and Roth 52 Nonetheless, the introspective and subjective experiences (i.e., significant changes in perception, cognition, affect, volition, and somesthesia)Reference Griffiths, Richards, McCann and Jesse 16 induced by this compound may go beyond the dosage, pharmacokinetic, and pharmacodynamic mechanisms, as discussed in the next paragraph.
Mystical experience and personality domains
During PAP, therapists aim to support patients to access an enduring mystic state where they can reprocess unconscious memories. Music and a supportive environment during PAP facilitate this process, increasing psychological and cognitive flexibility, which is the main mediator of psilocybin benefits in mood disorders.Reference Davis, Barrett and Griffiths 53 During these processes, rigid thought patterns are loosened and experiences of ego-dissolution and deep universal connections are reported.Reference Smigielski, Scheidegger, Kometer and Vollenweider 54 Within the phenomenon of ego-dissolution, patients experience a profound disintegration of their perception of being a separate self from their surroundings. Ego-dissolution involves the breakdown of typical cognitive structures that contribute to individual consciousness, ultimately leading to a sense of loss of personal identity, as well as a more fluid perception of subjective experience.Reference Letheby and Gerrans 55 However, under these conditions, there is a possibility of individuals being influenced in their thoughts, and there have been occasional attempts to brainwash individuals.Reference Dimsdale 56 One way to prevent inappropriate behaviors during PAP sessions could be to ensure the constant presence of at least two therapists per session. Despite these negative occurrences, we emphasize that mystical experiences appear relevant to decrease depressive ruminations and increase empathy, self-acceptance, social life, and openness. A single PAP session has indeed been found to decrease neuroticism and increase both extroversion and openness when personality was assessed using the Revised NEO Personality Inventory (NEO-PI-R) at 3 months of follow-up.Reference Erritzoe, Roseman and Nour 57 While standard antidepressants can also slightly mitigate neuroticism in MDD, extroversion and openness are specifically related to the effect of PAP.Reference Jylhä, Ketokivi and Mantere 58 , Reference Tsigkaropoulou, Michopoulos, Porichi, Dafnas, Serretti and Ferentinos 59 These variations in personality domains, if durable, reshape the patient’s interactions with the environment and may explain the sustained effect of psilocybin over time only after a few sessions. On the other hand, the possibility of long-lasting personality effects may raise ethical issues.Reference Griffiths, Johnson and Carducci 32 , Reference Erritzoe, Roseman and Nour 57 We underline that the available studies have a maximum follow-up duration of 12 months,Reference Gukasyan, Davis and Barrett 60 with only two secondary analyses providing data on 4.5 years of follow-up,Reference Agin-Liebes, Malone and Yalch 61 , Reference Ross, Agin-Liebes and Lo 62 This temporal limitation underscores the necessity for extended longitudinal studies to comprehensively evaluate the durability of psilocybin’s therapeutic benefits.
The relevance of these findings derives from the fact that they overcome the traditional assumption that personality changes can only occur slowly and gradually.Reference Roberts, Luo, Briley, Chow, Su and Hill 63 The effect of psilocybin appears even more intriguing when considering the stability of personality traits in healthy adults, as well as the greater rigidity of personality in patients with psychiatric disordersReference McNeil and Reddon 64 compared to the general population.Reference Roberts, Walton and Viechtbauer 65 According to the above, we glimpse the potential benefits of using the PAP paradigm in personality disorders, especially considering that to date no drugs are specifically approved to treat these conditions. However, we also underline that there is currently no experimental evidence from clinical trials supporting this hypothesis. Future research would help to bridge the gap between psychopathology and neurobiology, by studying the possible link between changes in psychopathological dimensions of personality (assessed, for instance, with the NEO-PI-R or the Personality Inventory for DSM-5 (PID-5)) and variations in specific functional brain networks induced by psilocybin in neuroimaging studies. Despite neuroplasticity phenomena mainly occurring in the prefrontal cortex, amygdala, and hippocampus,Reference Ling, Ceban and Lui 66 the molecular mechanisms underlying these effects remain essentially unknown.
Psychedelic-assisted psychotherapy
According to the current trial protocols, psilocybin is typically administered alongside a psychological support called PAP. The only exception is a trial of psilocybin for OCD where no concomitant psychotherapy or psychosocial intervention was provided to participants.Reference Moreno, Wiegand, Taitano and Delgado 67
PAP includes three phases: preparation, psilocybin session, and integration. During preparation, patients are given information about the upcoming drug therapy session and guidance on how to maximize benefits while minimizing adverse events. This increases patients’ expectations and suggestibility toward the treatment, posing challenges in obtaining accurate informed consent. Since the surrounding setting significantly influences the experience and the adverse events, PAP sessions are delivered in a calm and relaxing environment with a preselected music program. If future trials confirm the importance of these setting requirements, this could limit widespread clinical application, as only a few healthcare centers may be adapted in a feasible way, and provide the personnel needed. In the weeks after treatment, psychotherapy is used to integrate thoughts, unconscious memories, and other psychopathological phenomena that arise during the sessions.Reference Barnett and Greer 68 While cognitive-behavioral therapies (CBTs) have the strongest evidence in PAP,Reference Yaden, Earp, Graziosi, Friedman-Wheeler, Luoma and Johnson 69 the unconscious processes during session and integration phases are also related to psychodynamic theories. Despite differences, PAP sessions contain elements of psychodynamic treatment where unconscious material is revealed. In the integration phase, patients report to nondirective therapists all thoughts and perceptions previously arisen without exerting any censorship or giving a conscious direction as if they were free associations, an essential tool of psychoanalytical practices.Reference Rabeyron and Entropy 70 It is indeed interesting to consider that elements from different psychotherapeutic approaches merge into an innovative approach that is, however, rooted in previous theories. PAP may offer another potential advantage. Traditional psychotherapeutic interventions often require multiple weekly sessions, sometimes lasting up to 12 months, to achieve a therapeutic effect.Reference Stoffers-Winterling, Völlm, Rücker, Timmer, Huband and Lieb 71 Intriguingly, when combined with psilocybin, enduring benefits over even 6 months can be achieved after only one or two sessions, resulting in less time consuming and potentially more cost-effective for the healthcare systems. Additionally, the rapid onset of action (as early as 8 hoursReference Ross, Agin-Liebes and Lo 62) and the lack of a daily pill intake can improve treatment adherence.
However, PAP shows some potential challenges. First, the psychological support hinders the quantification of psilocybin’s benefit itself. Given the paucity of studies without psychotherapy, the benefits of the drug itself remain to be demonstrated still if not associated with psychotherapy. Second, PAP is an operator-dependent approach, leading to significant heterogeneity and outcome differences. Third, future studies should determine the optimal psychotherapeutic approach in terms of intervention type and session frequency, as well as the possible benefits of different psychologically oriented interventions and settings. For instance, depressed patients with comorbid borderline personality disorder (BPD) were excluded from the majority of trials, while a study showed the benefits of PAP in this group.Reference Anderson, Danforth and Daroff 39 Possible integration of PAP with specific CBT approaches (e.g., dialectical behavioral therapy or DBT) may further improve outcomes in patients with personality disorders. Furthermore, integrating PAP with specific skills of the DBT modules (i.e., mindfulness, distress tolerance, emotion regulation, and interpersonal effectiveness) might be beneficial for all patients, providing them with tools to deal with unpleasant memories or to face changes to achieve new goals in their lives.Reference Yaden, Earp, Graziosi, Friedman-Wheeler, Luoma and Johnson 69 Undoubtedly, significant economic and human resources are needed in the short term to train and certify clinicians and to set the environment for preparatory and integrative sessions. This may constitute a challenge in implementing PAP in developing countries or culturally diverse nations. Developing a culturally adapted version of PAP is crucial for worldwide accessibility, as it was investigated mostly in the United States (US) and Western countries. Finally, yet importantly, as PAP sessions can last several hours or even an entire workday, working shifts will have to consider this aspect.
Evidence of efficacy, confounders, and limitations of clinical trials
The evidence previously presented should be interpreted considering that it derives from a mix of RCTs not always well-designed, non-randomized studies, open-label trials, and pilot studies. Details regarding the main findings and limitations of the available studies investigating psilocybin use in psychiatric disorders are summarized in Table 2.
Completed Clinical Trials and Secondary Analyses with Results Published in Peer-Reviewed Journals until December 2023
For some studies, some data is not available (i.e., p-value, effect size, SD, and MD).
Abbreviations: AE, adverse event; AIDS, acquired immune deficiency syndrome; BD, bipolar depression; BDD, body dysmorphic disorder; BDD-YBOCS, Yale Brown Obsessive Compulsive Scale Modified for Body Dysmorphic Disorder; BDI, Beck Depression Inventory total score; BDII, bipolar depression II; BSI, Brief Symptom Inventory; CI, confidence interval; df, degrees of freedom; DS, Demoralization Scale, DS-II, Demoralization Scale-II; ESC, escitalopram; F, F-statistic; GRID-HDRS, Grid-Hamilton Depression Rating Scale total score; HADS, Hospital Anxiety and Depression Scale total score; HAM-A, Hamilton Anxiety Rating Scale total score; h, hour; HS, healthy subjects; MADRS, Montgomery-Asberg Depression Rating Scale total score; MD, mean deviation; MDD, major depressive disorder; mth, month; N, sample size; NA, not available; NEO-PI-R, revised NEO Personality Inventory; OCD, obsessive-compulsive disorder; p, p-value; POFLE, Prediction Of Future Life Events task; PSY, psilocybin; QIDS, Quick Inventory of Depressive Symptomatology total score; QIDS-SR, Quick Inventory of Depressive Symptomatology-Self Reported total score; SD, standard deviation; STAI, State–Trait Anxiety Inventory total score; TAU, treatment as usual; TRD, treatment resistant depression; wk, week; YBOCS, Yale-Brown Obsessive Compulsive Scale; yr, year.
Research on MDD, anxiety and depressive symptoms associated with life-threatening cancer, and TRD showed the most robust evidence, supported by a non-randomized studyReference Sloshower, Skosnik and Safi-Aghdam 72 and several RCTs.Reference Carhart-Harris, Giribaldi and Watts 26 , Reference Grob, Danforth and Chopra 31 -Reference Ross, Bossis and Guss 33 , Reference Gukasyan, Davis and Barrett 60 , Reference Davis, Barrett and May 73 -Reference Von Rotz, Schindowski and Jungwirth 77 Open-label studiesReference Carhart-Harris, Bolstridge and Rucker 25 , Reference Anderson, Danforth and Daroff 39 , Reference Erritzoe, Roseman and Nour 57 , Reference Carhart-Harris, Roseman and Bolstridge 78 -Reference Agrawal, Emanuel, Richards, Richards, Roddy and Thambi 81 and two follow-up analysesReference Agin-Liebes, Malone and Yalch 61 , Reference Ross, Agin-Liebes and Lo 62 supported the overall positive findings of RCTs. Among all the studies conducted, five were pilot studies.Reference Carhart-Harris, Bolstridge and Rucker 25 , Reference Grob, Danforth and Chopra 31 , Reference Anderson, Danforth and Daroff 39 , Reference Sloshower, Skosnik and Safi-Aghdam 72 , Reference Lyons and Carhart-Harris 80 Concerning the outcome, two trials reported no significant difference in the antidepressant effect between psilocybin and escitalopramReference Carhart-Harris, Giribaldi and Watts 26 or placebo,Reference Sloshower, Skosnik and Safi-Aghdam 72 whereas another one showed improvement in depression only at month 6.Reference Grob, Danforth and Chopra 31 According to a recent meta-analysis, which included three RCTs and three open-label studies, the use of psilocybin (at doses ranging from 1 mg to 25 mg) to patients not currently taking any other psychotropic medications resulted in significant reductions in depressive symptoms.Reference Watford and Masood 38
However, these studies have significant limitations and do not clearly provide conclusive evidence on the antidepressant efficacy of psilocybin, particularly in the long term. Concerning the recruitment phase, there are clear limitations such as small sample sizesReference Carhart-Harris, Bolstridge and Rucker 25 , Reference Grob, Danforth and Chopra 31 -Reference Ross, Bossis and Guss 33 , Reference Anderson, Danforth and Daroff 39 , Reference Erritzoe, Roseman and Nour 57 , Reference Gukasyan, Davis and Barrett 60 , Reference Sloshower, Skosnik and Safi-Aghdam 72 -Reference Becker, Holze and Grandinetti 74 , Reference Von Rotz, Schindowski and Jungwirth 77 -Reference Agrawal, Emanuel, Richards, Richards, Roddy and Thambi 81 with lack of diversity among participantsReference Griffiths, Johnson and Carducci 32 , Reference Ross, Bossis and Guss 33 , Reference Anderson, Danforth and Daroff 39 , Reference Erritzoe, Roseman and Nour 57 , Reference Gukasyan, Davis and Barrett 60 , Reference Sloshower, Skosnik and Safi-Aghdam 72 , Reference Goodwin, Aaronson, Alvarez, Arden, Baker and Bennett 75 -Reference Carhart-Harris, Bolstridge and Day 79and potential selection biases.Reference Carhart-Harris, Giribaldi and Watts 26 , Reference Grob, Danforth and Chopra 31 , Reference Anderson, Danforth and Daroff 39 , Reference Sloshower, Skosnik and Safi-Aghdam 72 -Reference Becker, Holze and Grandinetti 74 , Reference Raison, Sanacora and Woolley 76 These issues limit the generalizability of findings and impede a comprehensive assessment of rare adverse events, as well as the precise evaluation of the number needed to harm, and the number needed to treat. One study only recruited healthy subjects.Reference Becker, Holze and Grandinetti 74 In terms of methodology, some studies showed inconsistent application of correction for multiple testing,Reference Carhart-Harris, Giribaldi and Watts 26 , Reference Becker, Holze and Grandinetti 74 no consideration of confounding factors,Reference Erritzoe, Roseman and Nour 57 , Reference Carhart-Harris, Roseman and Bolstridge 78 lack of randomization,Reference Sloshower, Skosnik and Safi-Aghdam 72 and relatively short-term follow-up periods were often observed,Reference Carhart-Harris, Bolstridge and Rucker 25 , Reference Carhart-Harris, Giribaldi and Watts 26 , Reference Grob, Danforth and Chopra 31 -Reference Ross, Bossis and Guss 33 , Reference Anderson, Danforth and Daroff 39 , Reference Erritzoe, Roseman and Nour 57 , Reference Sloshower, Skosnik and Safi-Aghdam 72 -Reference Agrawal, Emanuel, Richards, Richards, Roddy and Thambi 81 generally between one and 6 months after one or two single active psilocybin treatments. Only one RCT has a 12-month follow-up.Reference Gukasyan, Davis and Barrett 60 Furthermore, the intake of other antidepressants during follow-up periods could confound results, and it remains uncertain whether the maintenance of medium-term therapeutic effect can be solely attributable to the PAP.Reference Gukasyan, Davis and Barrett 60 Only two long-term 4.5-year follow-up studies are available, involving 4 and 14 patients, respectively.Reference Agin-Liebes, Malone and Yalch 61 , Reference Ross, Agin-Liebes and Lo 62 One of these shows a sustained reduction in demoralization,Reference Ross, Agin-Liebes and Lo 62 while the other presents the clinical response rates for depression and anxiety.Reference Agin-Liebes, Malone and Yalch 61 This lack of information on long-term safety, tolerability, and efficacy represents an important obstacle to the use of psilocybin in clinical practice, as mood disorders are typically chronic and recurrent. In terms of study design, the use of open-labelReference Carhart-Harris, Bolstridge and Rucker 25 , Reference Anderson, Danforth and Daroff 39 , Reference Erritzoe, Roseman and Nour 57 , Reference Carhart-Harris, Roseman and Bolstridge 78 -Reference Agrawal, Emanuel, Richards, Richards, Roddy and Thambi 81 and crossover designs,Reference Grob, Danforth and Chopra 31 -Reference Ross, Bossis and Guss 33 , Reference Becker, Holze and Grandinetti 74 , Reference Lyons and Carhart-Harris 80 as well as a single-dose protocol,Reference Grob, Danforth and Chopra 31 , Reference Ross, Bossis and Guss 33 , Reference Anderson, Danforth and Daroff 39 , Reference Sloshower, Skosnik and Safi-Aghdam 72 -Reference Von Rotz, Schindowski and Jungwirth 77 was frequently noted. Blinding procedures were not consistently robust,Reference Carhart-Harris, Giribaldi and Watts 26 , Reference Griffiths, Johnson and Carducci 32 , Reference Gukasyan, Davis and Barrett 60 , Reference Sloshower, Skosnik and Safi-Aghdam 72 -Reference Raison, Sanacora and Woolley 76 and comparison with placebo or standard treatments was lacking in many studies.Reference Carhart-Harris, Bolstridge and Rucker 25 , Reference Carhart-Harris, Giribaldi and Watts 26 , Reference Grob, Danforth and Chopra 31 -Reference Ross, Bossis and Guss 33 , Reference Anderson, Danforth and Daroff 39 , Reference Erritzoe, Roseman and Nour 57 , Reference Gukasyan, Davis and Barrett 60 , Reference Sloshower, Skosnik and Safi-Aghdam 72 , Reference Davis, Barrett and May 73 , Reference Goodwin, Aaronson, Alvarez, Arden, Baker and Bennett 75 -Reference Agrawal, Emanuel, Richards, Richards, Roddy and Thambi 81 Potential detection bias was sometimes observed due to differences in outcome measurement between the treatment and control groups.Reference Grob, Danforth and Chopra 31 , Reference Ross, Bossis and Guss 33 In some instances, control groups consisted of waiting lists rather than active comparators,Reference Gukasyan, Davis and Barrett 60 , Reference Davis, Barrett and May 73 and therapeutic settings were sometimes not consistently provided.Reference Becker, Holze and Grandinetti 74 , Reference Raison, Sanacora and Woolley 76 Finally, in one RCT not all questionnaires used for data collection were validated, introducing an additional source of bias.Reference Griffiths, Johnson and Carducci 32
Evidence of efficacy for OCD,Reference Moreno, Wiegand, Taitano and Delgado 67 body dysmorphic disorder (BDD),Reference Schneier, Feusner and Wheaton 82 alcohol dependence,Reference Bogenschutz, Forcehimes, Pommy, Wilcox, Barbosa and Strassman 83 and tobacco addictionReference Johnson, Garcia-Romeu, Cosimano and Griffiths 84 , Reference Johnson, Garcia-Romeu and Griffiths 85 is promising but limited due to the absence of RCTs. To address this limitation, two RCTs assessing the effects of PAP in alcohol-dependent volunteersReference O’Donnell, Mennenga and Owens 86 and smokers (NCT01943994) have been conducted, albeit results have not been published yet. To date, no study has investigated PAP treatment for PTSD. An open-label pilot study of psilocybin for bipolar depression II (BDII) (NCT05065294) is currently recruiting participants, while another one (NCT04433845) with a single-dose design has been already published.Reference Aaronson, Van Der Vaart and Miller 87 Additionally, two qualitative analyses of follow-up interviewsReference DellaCrosse, Pleet and Morton 88 and web-surveyReference Morton, Sakai, Ashtari, Pleet, Michalak and Woolley 89 of anecdotal use of psilocybin in individuals with putative BD reported that the drug was perceived to be more helpful than harmful. However, it is important to note several limitations of qualitative studies including self-reported diagnosis, selection, recall bias, and reporting bias, which may primarily emphasize positive experiences limiting the understanding of negative ones.
Besides these intrinsic limitations of the study design, another common limitation among available trials is the strict inclusion criteria, which severely reduces the results’ generalizability. Common exclusion criteria include a family history of psychotic and bipolar disorders, current psychotic symptoms, concomitant antidepressant drugs during PAP, and active suicidal ideation or intent.Reference Griffiths, Johnson and Carducci 32 The exclusion of patients with psychotic symptoms and/or suicidal ideation aims to avoid the rare possibility of inducing psychotomimetic adverse events and suicidal behavior in patients with congruent ideation. However, excluding depressed patients treated with other antidepressants may be considered overly conservative, preventing a comprehensive understanding of psilocybin’s safety and effects in combination therapy, as well as the necessary tapering or washout periods to avoid pharmacological interactions upon switching medications. To the best of our knowledge, only two recent clinical trials (NCT03429075 and NCT03912974) included two separate treatment sessions with psilocybin and an SSRI. In the former, there was no concomitant administration of the two drugsReference Carhart-Harris, Giribaldi and Watts 26; in the latter, psilocybin was administrated only on the last day of the two-week escitalopram pretreatment period.Reference Becker, Holze and Grandinetti 74 Consequently, the relative efficacy of psilocybin in combination with another antidepressant has not yet been established in RCTs. Moreover, standard antidepressants typically show limited efficacy in reducing suicidal ideation in the first phase of treatment.Reference Olgiati and Serretti 90 In this regard, one of the mentioned clinical trials compared psilocybin to the SSRI escitalopram.Reference Carhart-Harris, Giribaldi and Watts 26 The study did not demonstrate the superiority of psilocybin over escitalopram in reducing depressive symptoms, its primary outcome. Although secondary outcomes, including suicidal ideation, clinical remission, other measures of depressive symptoms, anxiety, and anhedonia, tended to favor psilocybin, the analysis was not corrected for multiple comparisons. Therefore, drawing firm conclusions from these findings may be questionable.Reference Carhart-Harris, Giribaldi and Watts 26 In terms of safety, psilocybin was better tolerated than escitalopram,Reference Carhart-Harris, Giribaldi and Watts 26 although the latter contributed to mitigating psilocybin-induced acute autonomic adverse events in the study arm evaluating the response to psilocybin after pretreatment with escitalopram.Reference Becker, Holze and Grandinetti 74 Although this finding does not result from a sustained and combined drug administration, it suggests that combining psilocybin with a standard antidepressant may not only be safe but also beneficial in terms of side effects. However, this may not apply to all antidepressants, and potential interactions should be considered carefully. For instance, since psilocin is metabolized by the liver monoamine oxidase (MAO),Reference Dinis-Oliveira 91 MAO inhibitors may intensify the effects, and this combination should be avoided. Conversely, a recent retrospective online survey found that psilocybin’s effect was attenuated up to 3 months after discontinuing SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs).Reference Gukasyan, Griffiths, Yaden, Antoine and Nayak 92 This attenuation might be due to postsynaptic serotonergic receptor downregulation following chronic antidepressant use.Reference Bonson and Murphy 93 Thus, regardless of the drug class, attention should be paid to the duration of standard antidepressant treatment: an acute administration may intensify the psychedelic effect and exacerbate adverse events, whereas a chronic administration may decrease the therapeutic effects of psilocybin.
Another challenge is conducting high-quality trials with a blinded control group treated with a psychoactive placebo that mimics subjective experiences and potential adverse events during PAP. Additionally, enhancing our understanding of how placebo effects influence psilocybin’s antidepressant efficacy could be achieved by using active comparators like ketamine, which induce similar immediate antidepressant response rates (71% at 28 hours for ketamine vs. 69% at 48 hours for psilocybin)Reference Zarate, Singh and Carlson 94 to assist with blinding, whereas it typically does not produce the sustained antidepressant response of psilocybin (35% at week 1 for ketamine vs. 71% at 1 month for psilocybin).Reference Davis, Barrett and May 73 , Reference Zarate, Singh and Carlson 94 , Reference Het Rot, Collins and Murrough 95 The difficulty of blinding studies on psychedelics also includes the possibility that positive results of psilocybin may have been enhanced by a nocebo effect in the control group. To reduce the impact of the nocebo effect, it has been recommended that in clinical trials, every patient randomized should receive an effective dose of psilocybin after the primary endpoint is assessed.Reference Mertens, Koslowski and Betzler 96 Furthermore, overcoming performance and detection bias in future studies will be of valuable importance, given the subjective effects induced by psilocybin and the self-rated scales used to detect them. In this respect, excluding participants with prior psychedelic exposure is essential to reduce expectancy bias, as many patients included in clinical trials reported previous psychedelic use.
Addressing these limitations will be essential for establishing the efficacy and safety profile of psilocybin as a treatment for psychiatric disorders.
Ethical challenges and legal considerations
Despite the therapeutic potential, psilocybin remains a prohibited and controlled substance in many countries. Nowadays, the legal use of psilocybin is limited to a few countries such as Jamaica, and the Netherlands, as well as in the context of research clinical trials.
As clinical studies yield promising results, the benefits and popularity of this psychedelic are growing faster than the ethical and legislative processes necessary for its proper use. An estimated 21 million people in the US use psilocybin, with some stating they use it for recreational purposes and others for self-medication.Reference Krebs and Johansen 97 The pressing need for novel therapeutic options for treatment-resistant psychiatric disorders is leading many patients to self-administer this drug, rather than waiting for further evidence of efficacy, legal medical, and protected access.Reference Pilecki, Luoma, Bathje, Rhea and Narloch 98 Social and cultural stigma, arising from both recreational and therapeutic misuse, presents another significant barrier to the potential use of psilocybin in clinical practice.
An ethical issue that may arise if psilocybin is approved by regulatory authorities for medical use is the need to standardize access to PAP sessions. If the benefits of this drug extend beyond psychiatry to conditions such as migraine headaches, organ transplantation, cancer, and immune diseases,Reference Barnett and Greer 68 ensuring fair access to treatment will be crucial. Priority should likely be given to life-threatening conditions initially (e.g., TRD with suicidal ideation and cancer).
A final issue that may slow the approval of psilocybin for medical use is the impossibility of patenting this drug since it is a naturally occurring compound. Therefore, psilocybin is not attractive to pharmaceutical companies, and the high involvement of institutional stakeholders is important.
Discussion
Despite the issues and challenges discussed above, there is increasing evidence suggesting the therapeutic potential of psilocybin in several conditions, characterized by a transdiagnostic profile with internalizing symptoms and ruminations. In depression, common ruminations include passive and negative thoughts about feelings of guilt, inefficacy, negative topics, and self-criticism.Reference Kennedy, Dunlop, Craighead, Nemeroff, Mayberg and Craighead 99 Ruminative brooding was consistently linked to a more severe substance use profile,Reference Memedovic, Slade and Ross 100 while ruminations about one’s obsessions can make obsessions even more intrusive and ego-dystonic in OCD.Reference Flaherty, Katz and Chosak 101
Psilocybin is typically administered for a few weeks, a considerably shorter duration compared to treatment with SSRIs/SNRIs, which can last several months or years to show and maintain antidepressant effects.Reference Moret, Isaac and Briley 102 Despite this more desirable shorter treatment period, PAP needs a specific therapeutic setting, making its administration more complicated compared to standard antidepressants that are generally taken by patients at home.
In our opinion, the potential benefits of psilocybin may also be considered with cautious optimism in other conditions, such as autism spectrum disorder (ASD). LSD showed potential efficacy in ASD during the “first wave” of psychedelic research.Reference Markopoulos, Inserra, De Gregorio and Gobbi 103 Psilocybin’s empathogenic effects may alleviate social anxiety, and depression, as well as rigid cognitive and behavioral patterns associated with ASD while increasing emotional empathy and sociability. Given the significant impact of social withdrawal as an early manifestation in various neuropsychiatric disorders, and its trans-diagnostic association with a decreased likelihood of short-term symptom remission,Reference Oliva, Fanelli and Kasper 104 the use of psilocybin to engage directly with social impairments presents a compelling therapeutic avenue. Additionally, a recent preclinical research involving a rat model reported that serotonin-modulating drugs such as psilocybin may be effective in ameliorating ASD-related cognitive deficits.Reference Buzzelli, Carbone and Manduca 105 Based on the evidence of psilocybin’s efficacy in ameliorating ego-dystonic obsessions in OCD,Reference Moreno, Wiegand, Taitano and Delgado 67 it may also be useful in reducing the pervasive interests and repetitive behaviors in ASD, though obsessive and compulsive-like symptoms in ASD differ from those in OCD and present unique psychopathological experiences.Reference Scala, Biondi, Serretti and Fabbri 106 While these effects are desirable in ASD, a potential challenge of PAP in this population could be the risk of triggering aggressive behavior due to the difficulties in interacting with therapists and communicating the deeper consciousness contents.Reference Bender, Cobrinik and Faretra 107 Considering that psychotic experiences are significantly higher in people with ASD compared to neurotypical individuals, another risk of using PAP in the ASD population may be related to the rare psychotic-like symptoms potentially induced by psilocybin.Reference Kiyono, Morita and Morishima 108 Therefore, a tailored PAP protocol for neurodevelopmental disorders may involve micro-dosing to minimize adverse events, and repeated sessions to facilitate the processing of unconscious material.
Nevertheless, before implementing psilocybin in the real world, further evidence of its safety and efficacy is required to support informed clinical decision-making. Future well-powered and designed RCTs should randomize patients to receive PAP, standard antidepressant drugs (i.e., SSRIs or SNRIs), and/or psychotherapy (i.e., CBT). Standardized psychometric scales should be used to assess symptom improvement/remission as the primary outcome. To ensure the validity of results, the assessment should be conducted at baseline, approximately 1 month after treatment initiation (to compare the onset of action), and periodically up to 1 year (to evaluate medium-term effects). Double-blinding procedures should be maintained throughout the study duration and the follow-up to eliminate potential detection biases. Considering that the different time periods between PAPs may impact treatment outcomes, RCTs should compare psilocybin effects when used with various time intervals between dosing sessions, such as once a week or once a month. Furthermore, RCTs may identify distinct subpopulations responding optimally to psilocybin, SSRIs/SNRIs, or CBT. By evaluating the impact of assignment to one of these three treatment groups on the outcomes, we might be able to explore whether these therapeutic pathways serve as the causal mediators through which treatment effectiveness is achieved.
We need to further investigate dose optimization, the optimal duration of washout periods to sustain the therapeutic effect between PAP sessions, the ideal number of sessions, as well as the most relevant elements and strategies of psychological intervention. This will allow us to understand if it is possible to minimize mild hallucinogenic effects and alterations in consciousness while still benefiting from neuroplasticity mechanisms. If this is possible, we would have a pure psychoplastogen agent.Reference Vargas, Meyer, Avanes, Rus and Olson 109 However, it is possible that the psychedelic experience is necessary to produce the therapeutic benefits, and neuroplasticity itself can partly contribute.Reference Moliner, Girych and Brunello 110 Since mystic experiences may direct the effects of neuroplasticity toward a beneficial change, providing supporting therapeutic settings seems necessary to obtain the full therapeutic potential of psilocybin. Enrolled patients should be willing to actively undergo this mystical experience, rather than passively hoping that psilocybin will change their thoughts and behavioral patterns. Therefore, patients’ motivation for this treatment and the therapeutic alliance with clinicians remain indispensable conditions for ensuring the benefits of the treatment itself.
A major effort from the scientific community is pivotal to strengthen boundaries, both legal and ethical, between the clinical and recreational use of psilocybin. This entails the development of appropriate ethical principles and guidelines, as well as legislative measures to prevent the misuse of psychedelics. Learning from the therapeutic use of ketamine, it is essential to carefully balance the risks and benefits associated with psilocybin.
It is important to temper excessive media enthusiasm surrounding psilocybin and comprehensively assess its potential interactions with other drugs, as well as the duration of its therapeutic effects. Furthermore, exploring other possible mechanisms of action, such as potential anti-inflammatory properties,Reference Nkadimeng, Steinmann and Eloff 111 may provide additional support for benefits in various disorders, including depressiveReference Benedetti, Zanardi and Mazza 112 and anxiety disorders.Reference Elnazer, Sampson and Baldwin 113
Conclusions
This review critically examined essential aspects related to the implementation of psilocybin in real-world settings, extending beyond its efficacy in treating major psychiatric disorders. While further evidence of efficacy is needed for the treatment of OCD and SUD, the use of psilocybin may present a potential alternative to current antidepressants, improving depressive and anxiety symptoms with mild and transient side effects, as well as a shorter onset of action and treatment duration. However, the integration of psilocybin into clinical practice still faces significant challenges, including the need for larger, well-powered RCTs to validate its efficacy and safety in a comprehensive manner. These future studies should also explore optimal dosing, treatment frequency, and the integration of psychological therapies to maximize therapeutic benefits. Moreover, it is imperative to establish clear ethical and legal frameworks to differentiate clinical use of psilocybin from its recreational misuse. Advancing psilocybin research will therefore require a concerted effort to accumulate robust, evidence-based data supporting its therapeutic application in psychiatry. This endeavor will not only help delineate the precise therapeutic niche of psilocybin but also potentially augment the armamentarium of available psychiatric treatments.
Ethical considerations
Since this review included only published data, ethics approval was not sought.
Funding and acknowledgments
This work was supported by #NEXTGENERATIONEU (NGEU) and funded by the Italian Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006)—a multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553, October 11, 2022).
Author contribution
Conceptualization: A.S., C.F., M.S., G.F.; Data curation: A.S., C.F., M.S., G.F.; Funding acquisition: A.S., C.F., M.a.P.S.(.5.M., G.F.; Investigation: A.S., C.F., M.S., G.F.; Methodology: A.S., C.F., M.S., G.F.; Project administration: A.S., C.F., G.F.; Resources: A.S., C.F., M.S., G.F.; Software: A.S., G.F.; Supervision: A.S., A.A., A.P., C.F., L.F., G.F.; Validation: A.S., A.A., A.P., C.F., L.F., M.S., G.F.; Writing – review & editing: A.S., A.A., A.P., C.A., C.F., G.D.L., D.D.R., M.a.P.S.(.5.M., L.F., M.M., M.F., M.S., P.F., G.F.; Writing – original draft: A.A., A.P., L.F., M.S.; Visualization: C.F., M.S.; Formal analysis: M.S.
Competing interest
AS is or has been a consultant to or has received honoraria or grants unrelated to the present work from Abbott, AbbVie, Angelini, Astra Zeneca, Clinical Data, Boehringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, InnovaPharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, Servier, and Taliaz. CF was a speaker for Janssen. The other authors declare no potential conflicts of interest.
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