Palliative care patients' attitudes and openness towards psilocybin-assisted psychotherapy for existential distress.

Introduction: Patients with incurable illnesses often experience existential distress, profoundly impacting their well-being. Current medical approaches have limitations in addressing these burdens. Psilocybin, a promising psychedelic compound, may offer therapeutic benefits. This pilot survey study aimed to investigate the attitudes and openness toward psilocybin-assisted psychotherapy (PAT) among patients with incurable illnesses. The objective is to assess patients' attitudes toward PAT and identify potential barriers and concerns, including exploring the association between beliefs in psilocybin's therapeutic benefits and interest in receiving this treatment. Methods: The survey study was conducted at the Tampa General Hospital Palliative Care Outpatient office in the United States. Participants were 32 English-fluent patients, aged 18 or older, with incurable illnesses. The survey included demographic questions, a validated tool to measure existential distress, and questions about knowledge and concerns regarding psilocybin. Attitudes toward PAT and interest in its future use were assessed using Likert scale responses. Results: Among the 31 analyzed participants, 51.6% expressed interest in future psilocybin treatment, while 32.3% did not indicate interest. Belief in the psilocybin's therapeutic benefits for stress and anxiety significantly correlated with interest in use. Concerns included risk of psychosis, lack of trained providers, and potential for exploitation. No demographic factors were associated with interest or levels of distress. Conclusions: This pilot study provides insights into the attitudes and concerns toward PAT among patients with incurable illnesses. Over half of participants expressed interest. However, concerns regarding its use were identified, with patients' concern for the risk of exploitation associated with PAT as an especially novel concern documented in this patient population. This highlighted the need for further education of risks and benefits or PAT by trained clinicians and rigorous training of clinicians with the establishment of safeguards against exploitation. Further research is necessary to explore the potential benefits of PAT and related non-psilocybin psychedelic compounds in addressing existential distress among patients with incurable illnesses.

Perspectives and preliminary experiences of psychedelics for the treatment of eating disorders: A systematic scoping review.

OBJECTIVE: Research regarding the therapeutic application of psychedelics and psychedelic-assisted psychotherapy in the treatment of eating disorders (EDs) has begun to emerge. This systematic scoping review aimed to map and synthesise the existing evidence regarding the participant reported efficacy and perspectives concerning psychedelics in the treatment of EDs, and to identify significant research gaps. METHOD: A systematic search was undertaken across several databases in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews guidelines. RESULTS: 1290 publications were identified, 1135 after duplicates removed, with 17 meeting full-eligibility criteria. Overall, findings suggested that most participants reported experiencing a meaningful reduction in their ED symptoms and having positive experiences or an openness to explore psychedelics as a treatment for ED symptoms, although some noted concerns of adverse effects and the importance of having psychological support to increase safety and efficacy. CONCLUSIONS: While preliminary research suggests psychedelics and psychedelic-assisted psychotherapy may be a viable treatment option for ED symptoms, further research with more robust research designs is required to increase confidence in its efficacy, generalisability, and safety as a therapeutic medium.

Psychedelic-assisted psychotherapy: where is the psychotherapy research?

RATIONALE: Psychedelic-assisted psychotherapy (PAP) has emerged as a potential treatment for a variety of mental health conditions, including substance use disorders and depression. Current models of PAP emphasize the importance of psychotherapeutic support before, during, and after ingestion of a psychedelic to maximize safety and clinical benefit. Despite this ubiquitous assumption, there has been surprisingly little empirical investigation of the "psychotherapy" in PAP, leaving critical questions about the necessary and sufficient components of PAP unanswered. OBJECTIVES: As clinical trials for psychedelic compounds continue the transition from safety- and feasibility-testing to evaluating efficacy, the role of the accompanying psychotherapy must be better understood to enhance scientific understanding of the mechanisms underlying therapeutic change, optimize clinical outcomes, and inform cost-effectiveness. RESULTS: The present paper first reviews the current status of psychotherapy in the PAP literature, starting with recent debates regarding "psychotherapy" versus "psychological support" and then overviewing published clinical trial psychotherapy models and putative models informed by theory. We then delineate lessons that PAP researchers can leverage from traditional psychotherapy research regarding standardizing treatments (e.g., publish treatment manuals, establish eligibility criteria for providers), identifying mechanisms of change (e.g., measure established mechanisms in psychotherapy), and optimizing clinical trial designs (e.g., consider dismantling studies, comparative efficacy trials, and cross-lagged panel designs). Throughout this review, the need for increased research into the psychotherapeutic components of treatment in PAP is underscored. CONCLUSIONS: PAP is a distinct, integrative, and transdisciplinary intervention. Future research designs should consider transdisciplinary research methodologies to identify best practices and inform federal guidelines for PAP administration.

Ketamine-Assisted Psychodynamic Psychotherapy.

This case report details the treatment of a longtime psychodynamic psychotherapy patient, with a particular focus on a ketamine-assisted psychotherapy (KAP) session, and how the progress achieved during this session compares with the literature on KAP. The patient is a 54-year-old woman with a history of multiple traumas, including sexual assault and life-threatening physical injuries, as well as a recent diagnosis of primary lateral sclerosis (PLS). For most of her life, she relied on extreme idealization of important people in her life as her primary defense mechanism, helping her to maintain physical and psychological survival. However, after a KAP session in January 2023 she discovered the consequences of her extreme idealizing tendencies. Among these was the creation of troubling double binds for the people she idealized, as well as the fomentation of conflict between these individuals with each other. Also unconscious was the secondary gain offered by her escalating physical symptoms and pain-that is, the ability to resolve conflicts between those she idealized-and how this secondary gain increased the likelihood of symptom exacerbations during periods of conflict. After the discovery of these unconscious tendencies during her KAP session, the patient has since been able to avoid extreme idealization of important people in her life and has subsequently experienced fewer episodes of exacerbation of her physical symptoms. Consistent with the opinions of clinicians and researchers published in the literature, the achievement of a psychedelic trance state appeared necessary for the success of the patient's KAP treatment.

Can research on entactogens contribute to a deeper understanding of human sexuality?

In recent years, scientific research into the therapeutic potential of psychedelic compounds has experienced a resurgence of interest. New studies have shown promising results, supporting the use of psychedelic drugs in treating various psychiatric disorders, including treatment-resistant depression, post-traumatic stress disorder, and even alcohol addiction. The FDA has recognized 3,4-methylenedioxymethamphetamine (MDMA) as a breakthrough therapy to treat symptoms of post-traumatic stress disorder. At the same time, interviews with recreational MDMA users have documented experiences of emotional intimacy while using MDMA, often without the desire for penetrative sex. However, some people have reported that MDMA increases their sexual arousal and specifically use it to enhance their sexual performance. This study aims to analyze current and planned research on the psychophysiological effects of entactogens on human sexuality. With their prosocial potential, the pharmacokinetic and neuroendocrine effects of entactogens may recreate the subjective experience of emotional intimacy, the initiation of intimate relationships, or even feelings of 'falling in love' with previously neutral individuals while under the influence of entactogens. This includes MDMA-induced sexual arousal-like effects observed through subjective behavioral perceptions of desire and arousal and specific physiological markers such as oxytocin and prolactin. Modern MDMA-assisted psychotherapy (MDMA-AP) protocols are transparent and follow strict ethical guidelines. However, despite these proposed ethical principles, little consideration has been given to the potential neurobehavioral effects of entactogens on the sexuality of participants in MDMA-AP protocols. The psychophysiological and sexual effects of entactogens should be discussed more openly in current MDMA-AP protocols, including the potential experience of the phenomenon of sexualized pharmacotransference.

The ego in psychedelic drug action - ego defenses, ego boundaries, and the therapeutic role of regression.

The ego is one of the most central psychological constructs in psychedelic research and a key factor in psychotherapy, including psychedelic-assisted forms of psychotherapy. Despite its centrality, the ego-construct remains ambiguous in the psychedelic literature. Therefore, we here review the theoretical background of the ego-construct with focus on its psychodynamic conceptualization. We discuss major functions of the ego including ego boundaries, defenses, and synthesis, and evaluate the role of the ego in psychedelic drug action. According to the psycholytic paradigm, psychedelics are capable of inducing regressed states of the ego that are less protected by the ego's usual defensive apparatus. In such states, core early life conflicts may emerge that have led to maladaptive ego patterns. We use the psychodynamic term character in this paper as a potential site of change and rearrangement; character being the chronic and habitual patterns the ego utilizes to adapt to the everyday challenges of life, including a preferred set of defenses. We argue that in order for psychedelic-assisted therapy to successfully induce lasting changes to the ego's habitual patterns, it must psycholytically permeate the characterological core of the habits. The primary working principle of psycholytic therapy therefore is not the state of transient ego regression alone, but rather the regressively favored emotional integration of those early life events that have shaped the foundation, development, and/or rigidification of a person's character - including his or her defense apparatus. Aiming for increased flexibility of habitual ego patterns, the psycholytic approach is generally compatible with other forms of psychedelic-assisted therapy, such as third wave cognitive behavioral approaches.

How psychedelic-assisted therapy works for depression: expert views and practical implications from an exploratory Delphi study.

As investigations into the efficacy of psychedelic-assisted psychotherapy to treat depression continue, there is a need to study the possible mechanisms of action that may contribute to the treatment's antidepressant effects. Through a two-round Delphi design, the current study investigated experts' opinions on the psychological mechanisms of action associated with the antidepressant effects of psychedelic-assisted psychotherapy and the ways such mechanisms may be promoted through the preparation, dosing, and integration components of treatment. Fourteen and fifteen experts, including both clinical psychedelic researchers and therapists, participated in Round 1 and Round 2 of the study, respectively. Thematic analysis identified nine important or promising 'mechanistic themes' from Round 1 responses: psychological flexibility, self-compassion, mystical experiences, self-transcendence, meaning enhancement, cognitive reframing, awe, memory reconsolidation and ego dissolution. These mechanisms were presented back to experts in Round 2, where they rated 'psychological flexibility' and 'self-compassion' to be the most important psychological mechanisms in psychedelic-assisted psychotherapy for depression. Strategies or interventions recommended to promote identified mechanisms during the preparation, dosing, and integration components of treatment were nonspecific to the endorsed mechanism. The findings from this study provide direction for future confirmatory mechanistic research as well as provisional ideas for how to support these possible therapeutic mechanisms.

Do Psychedelics Facilitate Emergence of Unconscious Psychological Processes?

Psychedelic substances have a long history of use in traditional healing and religious ceremonies worldwide and are increasingly being investigated for their possible therapeutic usage. However, there is still a lack of consensus regarding how best to characterize the psychological effects of psychedelics and how they bring about the positive therapeutic outcomes observed in clinical studies. The aim of this article is to review available evidence from quantitative and qualitative studies on psychedelic-assisted therapy, as well as neurobiological studies, in relation to the hypothesis that psychedelics facilitate the emergence of emotionally charged unconscious material, originally proposed by pioneering psychedelics researcher Stanislav Grof. The reviewed process studies of therapeutic mechanisms in psychedelic-assisted therapy and qualitative studies of treatment participants clearly indicate that the psychedelic experience is associated with the subjective experience of having increased access to and awareness of emotions, memories, and perceptions that are normally avoided or outside of conscious awareness. Brain-imaging studies point to several different neurobiological effects of psychedelics that might be related to these subjective psychological experiences. Available evidence also indicates that this process might constitute an important therapeutic mechanism in psychedelic-assisted therapy, worthy of further investigation.

Healing Words: Effects of Psychoeducation on Likelihood to Seek and Refer Psychedelic-Assisted Psychotherapy Among BIPOC Individuals.

Psychedelic-assisted psychotherapy (PAP) is gaining renewed interest as a treatment for various mental disorders. However, there has been limited Black, Indigenous, and People of Color (BIPOC) representation in PAP clinical trials, signaling the need for culturally consonant communication about the efficacy and safety of PAP. We randomly assigned 321 BIPOC and 301 non-Hispanic White participants to four different modes of psychoeducation (didactic, visual, narrative, hope-based) and tested effects on likelihood of seeking and referring others to PAP using ANCOVAS. The influences of different psychoeducation components on these likelihoods were also tested using hierarchical regression modeling. Regardless of psychoeducation mode, BIPOC participants were more likely to seek PAP than non-Hispanic White participants after psychoeducation. Further, information on physical safety and success rate of PAP uniquely predicted BIPOC participants' likelihood of seeking and referring others to PAP after psychoeducation. Our findings suggest that once provided psychoeducation, BIPOC participants are receptive to seeking or referring others to PAP. BIPOC participants also appear to prioritize physical safety and rate of success of PAP in these decisions. Stigma against PAP is likely not the primary barrier to recruitment of BIPOC individuals into PAP trials. Instead, researchers should conduct more psychoeducational outreach to diversify future trials.

"But the reality is it's happening": A qualitative study of eating disorder providers about psilocybin-assisted psychotherapy.

OBJECTIVE: This study invited providers who care for patients with eating disorders to inform engagement, communication, and collaboration with psilocybin-assisted psychotherapy interventions. METHOD: Medical and mental health providers who treat patients with eating disorders were recruited via professional referral networks and participant driven sampling from across California to participate in one of five focus groups. Discussion topics included prior knowledge of psychedelic therapy, interest/concerns related to psilocybin therapy, and opportunities for collaboration. Study team members completed iterative rounds of coding with a grounded theory approach. RESULTS: A total of 32 participants reported a range of familiarity with psychedelics. Some raised concerns about the risks of administering psilocybin to malnourished patients and to those with psychological comorbidities. Despite these concerns, participants were hopeful to see psilocybin therapy as a treatment for patients with eating disorders. In anticipating challenges, providers had concerns about equity in access to care among publicly insured and non-English speaking patients. They requested opportunities for continuing education about psilocybin therapy. DISCUSSION: Our findings demonstrate provider interest in psilocybin therapy for the treatment of patients with eating disorders. As psilocybin therapy interventions are developed, providers caring for patients with eating disorders value collaboration to improve longitudinal patient outcomes. PUBLIC SIGNIFICANCE: This study invited healthcare providers of patients with eating disorders to discuss their thoughts around the use of psilocybin-assisted psychotherapy in this population. Findings will help inform emerging psilocybin therapy clinical trials with the goal of successful translation and adoption in real world clinical settings.

Psilocybin for treatment-resistant depression without psychedelic effects: study protocol for a 4-week, double-blind, proof-of-concept randomised controlled trial.

BACKGROUND: Randomised controlled trials (RCTs) of psilocybin have reported large antidepressant effects in adults with major depressive disorder and treatment-resistant depression (TRD). Given psilocybin's psychedelic effects, all published studies have included psychological support. These effects depend on serotonin 2A (5-HT2A) receptor activation, which can be blocked by 5-HT2A receptor antagonists like ketanserin or risperidone. In an animal model of depression, ketanserin followed by psilocybin had similar symptomatic effects as psilocybin alone. AIMS: To conduct a proof-of-concept RCT to (a) establish feasibility and tolerability of combining psilocybin and risperidone in adults with TRD, (b) show that this combination blocks the psychedelic effects of psilocybin and (c) provide pilot data on the antidepressant effect of this combination (compared with psilocybin alone). METHOD: In a 4-week, three-arm, 'double dummy' trial, 60 adults with TRD will be randomised to psilocybin 25 mg plus risperidone 1 mg, psilocybin 25 mg plus placebo, or placebo plus risperidone 1 mg. All participants will receive 12 h of manualised psychotherapy. Measures of feasibility will include recruitment and retention rates; tolerability and safety will be assessed by rates of drop-out attributed to adverse events and rates of serious adverse events. The 5-Dimensional Altered States of Consciousness Rating Scale will be a secondary outcome measure. RESULTS: This trial will advance the understanding of psilocybin's mechanism of antidepressant action. CONCLUSIONS: This line of research could increase acceptability and access to psilocybin as a novel treatment for TRD without the need for a psychedelic experience and continuous monitoring.

Psychedelic Assisted Psychotherapy preparing your target using psychohistoriography: a Jamaican perspective.

The efficacy of psilocybin and other psychedelics as modes of treatment have been demonstrated through clinical trials and other studies in the management of a number of mental illnesses, including some treatment resistant cases. In Psychedelic Assisted Psychotherapy (PAP), psychedelics catalyze or enhance the experience fostered by psychotherapeutic methods. Psychohistoriographic Brief Psychotherapy, conceptualized by the late Professor Frederick Hickling in the 1970's in Kingston, Jamaica, offers a pathway for exploration in the Jamaican context. Applied to individuals, Psychohistoriographic Brief Therapy (PBT) has already shown success in patients with personality disorders in Jamaica through a process which includes documenting life experiences in a psychohistoriogram. In the De La Haye psilocybin Treatment Protocol (DPTP), micro-doses of crushed, dried psilocybin mushrooms are taken throughout an 8-week outpatient process of documenting the components of the psychohistoriogram, making use of the increased openness and empathy associated with the use of psychedelic agents. These sessions are followed by supervised in-office therapeutic/mystical doses of crushed, dried psilocybin mushrooms in the 9th week. Given the legal status and availability of psilocybin containing products in a few countries like Jamaica, there is a potential role for a regulated psychedelic industry contributing to the body of useful and rigorous clinical research which is needed in this area. Clients could benefit as we venture into this new frontier in psychiatry.

Psychologists' and psychotherapists' knowledge, attitudes, and clinical practices regarding the therapeutic use of psychedelics.

INTRODUCTION: This study explored the current knowledge, attitudes, and clinical practices regarding psychedelics among mental health professionals in California, where state legislation to decriminalize psychedelics has been proposed. METHOD: Two hundred thirty-seven mental health providers (74% female; mean age 54; 83% White; 46% psychologists) completed a 37-item online survey between November 2021 and February 2022, disseminated through local and state-wide professional organizations in California. RESULTS: Providers endorsed limited knowledge about the risks and benefits of psychedelic use (M = 4.7 and 5.4, respectively, with 10 = high knowledge) and inadequate knowledge to counsel patients on use (45%). Gaps in knowledge related to psychedelic drug scheduling and current use in clinical research were identified. Providers expressed support for additional psychedelic research (97%), approval of recreational (66%) and medical (91%) psychedelic use, belief in the potential therapeutic benefits of psychedelics (89%), and concerns about safety (33%) and potential psychiatric risks (27%). Results indicated that most providers discuss psychedelic use with patients (73%), yet many do not feel comfortable addressing the effects of use (49%). There were significant correlations between knowledge and attitudes towards psychedelics (r = 0.2, p = .006; r = 0.31, p < .001) and attitudes and clinical practices (r = 0.34, p < .001). CONCLUSIONS: Findings suggest that providers are interested in psychedelic-assisted treatments and hold favourable attitudes towards the therapeutic use of psychedelics yet lack the knowledge to appropriately counsel patients, highlighting the need for additional provider education about psychedelics.

Transformative experience and informed consent to psychedelic-assisted psychotherapy.

Just as psychedelic-assisted psychotherapy (PAP) represents a clinical innovation that may need to be accommodated with corresponding theoretical and methodological innovations, there is growing awareness that the tools, normative frameworks, and standard practices of our clinical ethics may also need to be adapted, renewed, or replaced to accommodate its unusual features. Drawing on L. A. Paul's work on "Transformative Experience," I argue that the acute and long-term effects that are repeatedly reported following the administration of psychedelic drugs, including in clinical contexts, are epistemically inaccessible at the point of deciding to take them. By virtue of both the so-called "mystical" experiences that frequently arise during PAP, and the long-term shifts to outlooks, values, and priorities that can follow treatment, the processes of decision-making that are normatively expected of patients run aground. If this framing is correct, then prospective patients cannot meet the requirement of understanding that is one of the principal analytic components of informed consent. The role of understanding in supporting two functions of informed consent-avoiding unauthorized trespass against patients and supporting values-aligned decision-making-is explored, and I argue that, while the normative standard for the first function may be met by extant suggestions for enhancing the consenting process for PAP, the latter function remains unattainable. In light of this, the consequences for the ethical preparation of prospective patients are considered.

Cost-effectiveness of psilocybin-assisted therapy for severe depression: exploratory findings from a decision analytic model.

BACKGROUND: There is growing evidence to support the use of the psychedelic drug psilocybin for difficult-to-treat depression. This paper compares the cost-effectiveness of psilocybin-assisted psychotherapy (PAP) with conventional medication, cognitive behavioural therapy (CBT), and the combination of conventional medication and CBT. METHODS: A decision model simulated patient events (response, remission, and relapse) following treatment. Data on probabilities, costs and quality-adjusted life years (QALYs) were derived from previous studies or from best estimates. Expected healthcare and societal costs and QALYs over a 6-month time period were calculated. Sensitivity analyses were used to address uncertainty in parameter estimates. RESULTS: The expected healthcare cost of PAP varied from £6132 to £7652 depending on the price of psilocybin. This compares to £3528 for conventional medication alone, £4250 for CBT alone, and £4197 for their combination. QALYs were highest for psilocybin (0.310), followed by CBT alone (0.283), conventional medication alone (0.278), and their combination (0.287). Psilocybin was shown to be cost-effective compared to the other therapies when the cost of therapist support was reduced by 50% and the psilocybin price was reduced from its initial value to £400 to £800 per person. From a societal perspective, psilocybin had improved cost-effectiveness compared to a healthcare perspective. CONCLUSIONS: Psilocybin has the potential to be a cost-effective therapy for severe depression. This depends on the level of psychological support that is given to patients receiving psilocybin and the price of the drug itself. Further data on long-term outcomes are required to improve the evidence base.

Exploring the Potential Utility of Psychedelic Therapy for Patients With Amyotrophic Lateral Sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is an aggressive, terminal neurodegenerative disease that causes death of motor neurons and has an average survival time of 3-4 years. ALS is the most common motor neuron degenerative disease and is increasing in prevalence. There is a pressing need for more effective ALS treatments as available pharmacotherapies do not reverse disease progression or provide substantial clinical benefit. Furthermore, despite psychological distress being highly prevalent in ALS patients, psychological treatments remain understudied. Psychedelics (i.e., serotonergic psychedelics and related compounds like ketamine) have seen a resurgence of research into therapeutic applications for treating a multitude of neuropsychiatric conditions, including psychiatric and existential distress in life-threatening illnesses. Methods: We conducted a narrative review to examine the potential of psychedelic assisted-psychotherapy (PAP) to alleviate psychiatric and psychospiritual distress in ALS. We also discussed the safety of using psychedelics in this population and proposed putative neurobiological mechanisms that may therapeutically intervene on ALS neuropathology. Results: PAP has the potential to treat psychological dimensions and may also intervene on neuropathological dimensions of ALS. Robust improvements in psychiatric and psychospiritual distress from PAP in other populations provide a strong rationale for utilizing this therapy to treat ALS-related psychiatric and existential distress. Furthermore, relevant neuroprotective properties of psychedelics warrant future preclinical trials to investigate this area in ALS models. Conclusion: PAP has the potential to serve as an effective treatment in ALS. Given the lack of effective treatment options, researchers should rigorously explore this therapy for ALS in future trials.

On the need for metaphysics in psychedelic therapy and research.

The essential proposal of this text is that psychedelic-induced metaphysical experiences should be integrated and evaluated with recourse to metaphysics. It will be argued that there is a potential extra benefit to patients in psychedelic-assisted therapy if they are provided with an optional, additional, and intelligible schema and discussion of metaphysical options at the integrative phase of the therapy. This schema (the "Metaphysics Matrix") and a new Metaphysics Matrix Questionnaire ("MMQ") stemming therefrom will be presented, the latter of which can also be used as an alternative or additional tool for quantitative measurement of psychedelic experience in trials. Metaphysics is not mysticism, despite some overlap; and certainly not all psychedelic experience is metaphysical or mystical-all three terms will be defined and contrasted. Thereafter psychedelic therapy will be presented and analysed in order to reveal the missing place for metaphysics. Metaphysics, with epistemology (theory of knowledge) and axiology (ethics and aesthetics), is a defining branch of Philosophy. Metaphysics, in contrast to mysticism, is considered to be based on argument rather than pure revelation. Thus, in psychedelic-assisted psychotherapy one sees here the potential bridge between reason-based philosophy and practical therapy-or, more broadly, with psychedelic-assisted psychotherapy there is the potential and mutually beneficial fusion of philosophy with practical science.

The Bright Side of Psychedelics: Latest Advances and Challenges in Neuropharmacology.

The need to identify effective therapies for the treatment of psychiatric disorders is a particularly important issue in modern societies. In addition, difficulties in finding new drugs have led pharmacologists to review and re-evaluate some past molecules, including psychedelics. For several years there has been growing interest among psychotherapists in psilocybin or lysergic acid diethylamide for the treatment of obsessive-compulsive disorder, of depression, or of post-traumatic stress disorder, although results are not always clear and definitive. In fact, the mechanisms of action of psychedelics are not yet fully understood and some molecular aspects have yet to be well defined. Thus, this review aims to summarize the ethnobotanical uses of the best-known psychedelic plants and the pharmacological mechanisms of the main active ingredients they contain. Furthermore, an up-to-date overview of structural and computational studies performed to evaluate the affinity and binding modes to biologically relevant receptors of ibogaine, mescaline, N,N-dimethyltryptamine, psilocin, and lysergic acid diethylamide is presented. Finally, the most recent clinical studies evaluating the efficacy of psychedelic molecules in some psychiatric disorders are discussed and compared with drugs already used in therapy.