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There is an increasing demand for effective treatments for depression, particularly for individuals grappling with treatment-resistant depression. Over recent years, a surge of interest has focused on exploring the safety and efficacy of psilocybin as a potential treatment for depression. However, preliminary findings from phase 2 studies have been inconclusive, prompting critical examination of issues such as maintaining blinding and the role of adjunctive psychotherapy. The maintenance of double-blinding and the role of adjunctive psychotherapy introduce biases that complicate the attainment of conclusive results in clinical research. Examining historical data reveals a recurrent pattern linked to the use of psychoactive substances, which starts with an excess of optimism and ends with general addictive behaviors and a heightened risk of serious public health problems. Considering these findings, a cautious and measured approach is imperative, given that the efficacy and safety of psilocybin treatment have yet to be unequivocally established. The potential for excessive optimism among researchers is a notable concern, as unwarranted enthusiasm may inadvertently facilitate the widespread adoption of this treatment without sufficient empirical support. In navigating the complexities of depression treatment, it is necessary to strike a balance between innovation and prudence to ensure evidence-based advancement of therapeutic approaches.

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Psychedelics (serotonergic hallucinogens) are psychoactive substances that can alter perception and mood, and affect cognitive functions. These substances activate 5-HT2A receptors and may exert therapeutic effects. Some of the disorders for which psychedelic-assisted therapy have been studied include depression, addiction, anxiety and post-traumatic stress disorder. Despite the increasing number of studies reporting clinical effectiveness, with fewer negative symptoms and, additionally, minimal side effects, questions remain to be explored in the field of psychedelic medicine. Although progress has been achieved, there is still little understanding of the relationship among human brain and the modulation induced by these drugs. The present article aimed to describe, review and highlight the most promising findings in the literature regarding the (putative) therapeutic effects of psychedelics.

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Abstract Objective Existing scales that seek to measure alterations in self-experience were developed based on studies conducted in developed countries. Therefore, the aim of this study was to evaluate the psychometric properties of the Ego Dissolution Inventory (EDI) after translating and adapting it for the Brazilian context. Methods The measure was translated by two translators fluent in both English and Portuguese, followed by back-translation into English to ensure there was no loss of meaning. The scale was used in an online survey exploring substance use. A total of 528 participants answered the full scale. We calculated the Kaiser-Meyer-Olkin (KMO) measure to evaluate sampling adequacy, then ran exploratory factor analysis (EFAs) to investigate the factor structure of the EDI. Results The scale showed acceptable psychometric properties, with excellent internal consistency and sampling adequacy for factor analysis. Kaiser-Guttman's criteria and Hull's method indicated a three-factor solution, while parallel analysis suggested a two-factor solution. All items showed salient loadings, with two items exhibiting cross-loading. Positive but weak correlations were found between EDI factors 1 and 2 and nature relatedness. Conclusions The validated scale showed solid psychometric properties, with potential differences in factor structure in relation to the English version. Considering validation is an ongoing process, it is recommended that studies be conducted comparing ego dissolution scores across distinct substances and different regions of the country.

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There has been a revival of research that studies the subjective effects of psychedelic drugs on humans. Areas of health science have been studying their possible therapeutic benefits, and psychological measurement instruments are being developed as the studies progress. However, these instruments currently suffer criticism regarding their number and evidence of psychometric quality. This study aims to review which psychometric instruments are available to assess subjective states induced by psychedelics. We systematically searched five databases (Web of Science, Academic Search Premier, EMBASE, CINAHL and PubMed) using psychometrics and psychedelics related terms identifying studies published from 1990 to 2021. Of 857 articles generated from the systematic-search, fifteen met our criteria and were included in the review, evaluating nine instruments: MEQ, 5D-ASC, HRS, PSI, EDI, CEQ, EBI, EDI and PIQ. Eight dealing with phenomenological aspects of the psychedelic experience and one as a screening tool for psychotic or manic episode. The purpose of each instrument, the number of items in each version, the type of scale and their elaboration process were described. The number of instruments used in psychedelic research is growing steadily, but there are still many other parts of the psychedelic experience that lack measurement.

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INTRODUCTION: Existing scales that seek to measure alterations in self-experience were based on studies conducted in developed countries. Therefore, the aim of this study was to evaluate the psychometric properties of the Ego-Dissolution Inventory (EDI), translate and adapt it to the Brazilian context. METHODS: Translation of the measure was made by two translators fluent in both English and Portuguese, with back-translation into English to ensure there was no loss of meaning. The scale was included in an online survey exploring substance use. A total of 528 participants answered the full scale. We calculated the Kaiser-Meyer-Olkin (KMO) measure to evaluate sampling adequacy, then ran Exploratory Analysis Factor (EFAs) to investigate the factor structure of the EDI. RESULTS: The scale showed acceptable psychometric properties, with excellent internal consistency and sampling adequacy for a factor analysis. Kaiser-Gutman's criteria and Hull's method pointed to a three-factor solution, while Parallel Analysis suggested a two-factor solution. All items showed salient loadings, with two items exhibiting cross-loading. Positive but weak correlations were found between EDI factors 1 and 2 and nature-relatedness. CONCLUSIONS: The validated scale showed solid psychometric properties, with potential differences in factor structure in relation to the English version. Considering validation as ongoing process, it is recommended to conduct studies comparing the scores of ego dissolution across distinct substances and different regions of the country.

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CONTEXT: People affected by serious illness usually experience suffering in its various dimensions, not only in the physical but also in the psychosocial and spiritual aspects. The interest in psychedelic-assisted therapies as a potential new therapeutic modality has increased since evidence suggests a significant impact of their use on the outcomes of patients with serious illness. OBJECTIVES: To systematically review the available evidence on the effects of psychedelic-assisted therapies for symptom control in patients diagnosed with serious illness. METHODS: The protocol of this systematic review has been prepared according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines. This review included randomized and non-randomized controlled trials published in peer-reviewed scientific journals. A comprehensive search for studies was carried out in the main scientific databases, including Web of Science, Scopus, Cochrane Library, PsycINFO, PubMed, CINAHL, and EMBASE. There were no limitations regarding the year or language of publication. RESULTS: The sample was composed of 20 studies. The results suggest positive effects of psychedelic-assisted therapies for symptom control in patients diagnosed with serious illness, with considerable safety of use. Most studies have been conducted with lysergic acid diethylamide, psilocybin, and N,N-dipropyltryptamine in cancer patients. The adverse effects reported were of physical and/or psychological nature and of mild to moderate intensity, transient, and self-resolutive. CONCLUSION: The evaluated evidence suggests positive effects of psychedelic-assisted therapies for symptom control in patients diagnosed with serious illness, especially regarding symptoms of psychological and spiritual nature.

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OBJECTIVE: To assess endocannabinoid (anandamide, AEA; 2-arachidonoylglycerol, 2-AG) plasma levels in healthy volunteers and in volunteers with social anxiety disorder (SAD) after a single oral dose of ayahuasca or placebo. METHODS: Post hoc analysis of endocannabinoid plasma levels (baseline, 90 and 240 min after drug intake) from two parallel-group, randomized, placebo-controlled trials. In Study 1, 20 healthy volunteers ingested ayahuasca (average 1.58 mg/ml dimethyltryptamine (DMT)) or placebo, and in Study 2, 17 volunteers with SAD received ayahuasca (average 0.680 mg/ml DMT) or placebo. RESULTS: A significant difference was observed in AEA concentrations in Study 2 after ayahuasca intake (Χ2 (2) = 6.5, p = 0.03, Friedman test), and near significant differences (increases) were observed between baseline and 90 (Z = 0, p = 0.06, Wilcoxon test) and 240 (Z = 10, p = 0.06) minutes after ayahuasca intake. CONCLUSIONS: Although our findings suggest that ayahuasca could modulate AEA levels in SAD patients, the high interindividual variability in both trials and the small samples preclude definitive conclusions. More research with larger samples is needed to better understand the effects of ayahuasca and other hallucinogens in the endocannabinoid system.

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Ayahuasca is a hallucinogenic/psychedelic traditionally used for ritual and therapeutic purposes. One such therapeutic use is related to Substance Use Disorders (SUDs). A previous systematic review of preclinical and human studies published until 2016 suggested that ayahuasca and its alkaloids have therapeutic effects in the treatment of SUDs. To conduct an update of this previous review. A systematic review of quantitative studies which analyzed the effects of ayahuasca and its alkaloids on drug use (primary outcome) and other measures (secondary outcomes) related to SUDs was conducted, including articles from 2016 to 2020. Nine studies (four preclinical, five observational) were included in the review. Preclinical studies in rodents reported reductions in amphetamine self-administration and anxiety, and in alcohol- and methylphenidate-induced conditioned place preference. Observational studies among healthy ritual ayahuasca users and patients with SUDs reported reductions in drug use, anxiety, and depression, and increases in quality of life and well-being. We replicated the findings of the previous review suggesting that ayahuasca and its alkaloids have therapeutic effects in the treatment of SUDs. However, translation of preclinical data to humans is limited, observational studies do not allow us to infer causality, and there is a lack of standardization on ayahuasca doses. Although promising, randomized, controlled trials are needed to better elucidate these results. The PROSPERO ID for this study is CRD42020192046.

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Rationale: Previous studies with the serotonergic hallucinogens LSD and psilocybin showed that these drugs induced changes in personality traits, such as increases in Openness. However, results are inconsistent, and the effects of ayahuasca on personality were never investigated in a controlled trial. Objectives: To assess the effects of ayahuasca on personality in two randomized, placebo-controlled trials in healthy volunteers. Methods: Data from two parallel-group, randomized, placebo-controlled trials in healthy volunteers were included. In the first trial, 15 volunteers ingested ayahuasca or placebo, while in the second trial 15 volunteers received placebo+ayahuasca or cannabidiol (CBD)+ayahuasca. Personality was assessed with the NEO-Five Factor Inventory (NEO-FFI) at baseline and 21 days post-treatment. Results: There were significant differences between groups in baseline Openness scores, but not on day 21. A significant increase in Openness scores was observed in the placebo + ayahuasca group in study 2. No other within-group differences were observed for any other domain. Conclusions: Ayahuasca produced inconsistent effects on personality since it induced significant increase in Openness 21 days post-drug intake only in one of the trials. The absence of significant differences in the other ayahuasca groups could be due to small sample sizes and baseline differences among groups. The effects of ayahuasca and other serotonergic hallucinogens on personality should be further investigated in clinical samples.

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Psychedelics or serotonergic hallucinogens are a group of substances that share the agonism of serotonergic 5-HT2A receptors as their main mechanism of action. Its main effects include changes in perception, cognitive process, and mood. Despite being used for centuries by different cultures in ritual contexts, these substances have currently aroused the interest of science and industry for their promising antidepressant, anxiolytic, and anti-addictive effects. Considering this evidence, this article aims to explore some of the possible health policy challenges to integrate these therapeutic tools into broad and heterogeneous health systems. As a main benefit, these substances produce rapid and enduring effects with the administration of single or few doses, which could lead to new treatment possibilities for patients with severe mental disorders resistant to the usual medications. The main challenge is associated with the fact that these substances remain scheduled in most countries and are associated with social stigma related to their recreational use (especially LSD and psilocybin). This situation makes it exceedingly difficult to conduct clinical trials, although international conventions allow such research. Ethically, this could be interpreted as a violation of human rights since thousands of people are prevented from having access to possible benefits. Interestingly, ritual ayahuasca use is more acceptable to the public than the use of psilocybin-containing mushrooms or LSD. The controlled, clinical use of LSD and psilocybin seems to be less criticized and is being explored by the industry. Rigorous scientific evidence coupled with industrial interests (LSD and psilocybin), together with respect for traditional uses (ayahuasca) and international conventions, seems to be the best way for these drugs to be integrated into health systems in the next years. Which highlights the need for an urgent dialogue between science, health system, society, and politics.

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Major depressive disorder (MDD) is among the most prevalent mental health disorders worldwide, and it is associated with a reduced quality of life and enormous costs to health care systems. Available drug treatments show low-to-moderate response in most patients, with almost a third of patients being non-responders (treatment-resistant). Furthermore, most currently available medications need several weeks to achieve therapeutic effects, and the long-term use of these drugs is often associated with significant unwanted side effects and resultant reductions in treatment compliance. Therefore, more effective, safer, and faster-acting antidepressants with enduring effects are needed. Together with ketamine, psychedelics (or classic or serotoninergic hallucinogens) such as lysergic acid diethylamide (LSD), psilocybin, and ayahuasca are among the few compounds with recent human evidence of fast-acting antidepressant effects. Several studies in the 1950s to 1970s reported antidepressive and anxiolytic effects of these drugs, which are being confirmed by modern trials (LSD, one trial; psilocybin, five trials; ayahuasca, two trials). The effects of these drugs appear to be produced primarily by their agonism at serotonin (5-hydroxytryptamine, 5-HT) receptors, especially the 5-HT2A receptor. Considering the overall burden of MDD and the necessity of new therapeutic options, the promising (but currently limited) evidence of safety and efficacy of psychedelics has encouraged the scientific community to explore more fully their beneficial effects in MDD.

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This article analyzes the use of science as a political tool in prohibitionist logic, adopting an externalist perspective. Prohibitionism strives to have its political-moral precepts be considered scientific, that is, the result of an ideologically neutral research process. The article analyzes the case of cannabis and psychedelics to show how prohibitionism has only resorted to "science" to hide its political-moral agenda, while ignoring the results of scientific research that did not fit its apriorisms. Finally, we argue that drug policies should be based on scientific evidence and on certain basic values - the defense of public health, social cohesion, Human Rights - such that an analysis in terms of power relations would allow us to better understand the contradictory relationships between science and drug policies.

Se analiza, desde una perspectiva externalista, el uso de la ciencia como herramienta política por parte de la lógica prohibicionista. El prohibicionismo trabaja para que sus preceptos político-morales sean considerados científicos, es decir, como el resultado de un proceso de investigación neutro a nivel ideológico. El artículo analiza el caso del cannabis y de los psicodélicos para mostrar cómo el prohibicionismo solo ha recurrido a la "ciencia" para ocultar su agenda político-moral, mientras ha ignorado todos los resultados de las investigaciones científicas que no se ajustaban a sus apriorismos. Finalmente planteamos que las políticas de drogas deben fundamentarse en la evidencia científica y en ciertos valores básicos ­defensa de la salud pública, de la cohesión social, de los Derechos Humanos­, por lo que un análisis en términos de relaciones de poder permitiría entender mejor las contradictorias relaciones entre ciencia y políticas de drogas.

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Se analiza, desde una perspectiva externalista, el uso de la ciencia como herramienta política por parte de la lógica prohibicionista. El prohibicionismo trabaja para que sus preceptos político-morales sean considerados científicos, es decir, como el resultado de un proceso de investigación neutro a nivel ideológico. El artículo analiza el caso del cannabis y de los psicodélicos para mostrar cómo el prohibicionismo solo ha recurrido a la "ciencia" para ocultar su agenda político-moral, mientras ha ignorado todos los resultados de las investigaciones científicas que no se ajustaban a sus apriorismos. Finalmente planteamos que las políticas de drogas deben fundamentarse en la evidencia científica y en ciertos valores básicos -defensa de la salud pública, de la cohesión social, de los Derechos Humanos-, por lo que un análisis en términos de relaciones de poder permitiría entender mejor las contradictorias relaciones entre ciencia y políticas de drogas.

This article analyzes the use of science as a political tool in prohibitionist logic, adopting an externalist perspective. Prohibitionism strives to have its political-moral precepts be considered scientific, that is, the result of an ideologically neutral research process. The article analyzes the case of cannabis and psychedelics to show how prohibitionism has only resorted to "science" to hide its political-moral agenda, while ignoring the results of scientific research that did not fit its apriorisms. Finally, we argue that drug policies should be based on scientific evidence and on certain basic values - the defense of public health, social cohesion, Human Rights - such that an analysis in terms of power relations would allow us to better understand the contradictory relationships between science and drug policies.

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In a recent issue of the BMC Psychiatry, the evidence of effectiveness of treatments for psychiatric conditions in end-stage cancer patients was reviewed (Johnson, 2018). The review was comprehensive, and included traditional and non-traditional/alternative treatments, including herbal medicines and spirituality. However, evidence showing that classic or serotonergic hallucinogens/psychedelics such as psilocybin and lysergic acid diethylamide (LSD) could be effective treatments for depressive and anxiety disorders in end-stage cancer was not included. In this commentary, we expand the information available on the original article by briefly reviewing data from recent placebo-controlled, double-blind, cross-over clinical trials showing evidence that administration of single (or few) doses of LSD and psilocybin was associated with rapid and sustained reductions in depressive and anxiety symptoms in patients with end-stage cancer and other life-threatening diseases (e.g., Bechterew's disease, Parkinson's disease, Celiac disease). Since these substances seem to produce rapid and sustained therapeutic effects with single (or few) doses and well tolerated, large-scale, prospective, multi-site studies of end-stage cancer and classical/serotonergic hallucinogens/psychedelics should be performed to improve our understanding of the therapeutic potentials of these drugs and their use on clinical practice.

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Ibogaine is a potent psychedelic alkaloid that has been the focus of intense research because of its intriguing anti-addictive properties. According to anecdotic reports, ibogaine has been originally classified as an oneirogenic psychedelic; i.e., induces a dream-like cognitive activity while awake. However, the effects of ibogaine administration on wakefulness (W) and sleep have not been thoroughly assessed. The main aim of our study was to characterize the acute effects of ibogaine administration on W and sleep. For this purpose, polysomnographic recordings on chronically prepared rats were performed in the light phase during 6 h. Animals were treated with ibogaine (20 and 40 mg/kg) or vehicle, immediately before the beginning of the recordings. Furthermore, in order to evaluate associated motor behaviors during the W period, a different group of animals was tested for 2 h after ibogaine treatment on an open field with video-tracking software. Compared to control, animals treated with ibogaine showed an increase in time spent in W. This effect was accompanied by a decrease in slow wave sleep (SWS) and rapid-eye movements (REM) sleep time. REM sleep latency was significantly increased in animals treated with the higher ibogaine dose. While the effects on W and SWS were observed during the first 2 h of recordings, the decrement in REM sleep time was observed throughout the recording time. Accordingly, ibogaine treatment with the lower dose promoted an increase on locomotion, while tremor and flat body posture were observed only with the higher dose in a time-dependent manner. In contrast, head shake response, a behavior which has been associated in rats with the 5HT2A receptor activation by hallucinogens, was not modified. We conclude that ibogaine promotes a waking state that is accompanied by a robust and long-lasting REM sleep suppression. In addition, it produces a dose-dependent unusual motor profile along with other serotonin-related behaviors. Since ibogaine is metabolized to produce noribogaine, further experiments are needed to elucidate if the metabolite and/or the parent drug produced these effects.

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[This corrects the article on p. 7 in vol. 12, PMID: 29403350.].

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Ever since the modern rediscovery of psychedelic substances by Western society, several authors have independently proposed that their effects bear a high resemblance to the dreams and dreamlike experiences occurring naturally during the sleep-wake cycle. Recent studies in humans have provided neurophysiological evidence supporting this hypothesis. However, a rigorous comparative analysis of the phenomenology ("what it feels like" to experience these states) is currently lacking. We investigated the semantic similarity between a large number of subjective reports of psychoactive substances and reports of high/low lucidity dreams, and found that the highest-ranking substance in terms of the similarity to high lucidity dreams was the serotonergic psychedelic lysergic acid diethylamide (LSD), whereas the highest-ranking in terms of the similarity to dreams of low lucidity were plants of the Datura genus, rich in deliriant tropane alkaloids. Conversely, sedatives, stimulants, antipsychotics, and antidepressants comprised most of the lowest-ranking substances. An analysis of the most frequent words in the subjective reports of dreams and hallucinogens revealed that terms associated with perception ("see," "visual," "face," "reality," "color"), emotion ("fear"), setting ("outside," "inside," "street," "front," "behind") and relatives ("mom," "dad," "brother," "parent," "family") were the most prevalent across both experiences. In summary, we applied novel quantitative analyses to a large volume of empirical data to confirm the hypothesis that, among all psychoactive substances, hallucinogen drugs elicit experiences with the highest semantic similarity to those of dreams. Our results and the associated methodological developments open the way to study the comparative phenomenology of different altered states of consciousness and its relationship with non-invasive measurements of brain physiology.

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Background Ayahuasca is a botanical hallucinogenic preparation traditionally used by indigenous populations of Northwestern Amazonian countries for ritual and therapeutic purposes. It is rich in β-carboline alkaloids and N,N-dimethyltryptamine (DMT). Preclinical, observational, and experimental studies suggest that ayahuasca and its alkaloids have anxiolytic and antidepressive effects. We recently reported in an open-label trial that ayahuasca administration was associated with significant decreases in depression symptoms for 2-3 weeks after the experimental session in 17 patients with treatment-resistant major depressive disorder. Objectives To investigate if the experiment had any long-lasting effects on patients Methods Eight patients were interviewed 4 to 7 years after ayahuasca intake. Results Our results suggest that ayahuasca was well tolerated and that symptom reductions were limited to a few weeks. Importantly, most patients believed that the experience was among the most important of their lives, even 4-7 years later. Discussion To the best of our knowledge, this is the first long-term follow-up of a clinical sample that participated in an ayahuasca trial. Further studies with different and repeated dosing should be designed to further explore the antidepressive and anxiolytic effects of ayahuasca.

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Abstract Background Ayahuasca is a psychoactive ethnobotanical concoction that has been used for decades by indigenous groups of the Northwestern Amazon and by syncretic religious organizations for ritual and therapeutic purposes. In the last two decades, it is being used worldwide in evolving practices. Ayahuasca seem to therapeutic effects, but controlled studies are lacking. Moreover, its safety and toxicity are not completely understood. Objectives To present an overview of the effects of ayahuasca based on the most recent human studies. Methods Narrative review. Results Ayahuasca administration in controlled settings appears to be safe from a subjective and physiological perspective, with few adverse reactions being reported. More frequent adverse reactions occur in non-controlled settings. Prolonged psychotic reactions are rare and seem to occur especially in susceptible individuals. Ayahuasca showed antidepressive, anxiolytic, and antiaddictive effects in animal models, observational studies, and in open-label and controlled studies. Discussion Ayahuasca administration in controlled settings appear to be safe. Moreover, ayahuasca seem to have therapeutic effects for treatment-resistant psychiatric disorders that should be further investigated in randomized controlled clinical trials. However, medical complications and cases of prolonged psychotic reactions have been reported, and people with personal or family history of psychotic disorders should avoid ayahuasca intake.