Interactive Effects of Ayahuasca and Cannabidiol in Social Cognition in Healthy Volunteers: A Pilot, Proof-of-Concept, Feasibility, Randomized-Controlled Trial.

BACKGROUND: Serotonergic hallucinogens and cannabinoids may alter the recognition of emotions in facial expressions (REFE). Cannabidiol (CBD) attenuates the psychoactive effects of the cannabinoid-1 agonist tetrahydrocannabinol. Ayahuasca is a dimethyltryptamine-containing hallucinogenic decoction. It is unknown if CBD may moderate and attenuate the effects of ayahuasca on REFE. PROCEDURES: Seventeen healthy volunteers participated in a 1-week preliminary parallel-arm, randomized controlled trial for 18 months. Volunteers received a placebo or 600 mg of oral CBD followed by oral ayahuasca (1 mL/kg) 90 minutes later. Primary outcomes included REFE and empathy tasks (coprimary outcome). Tasks were performed at baseline and 6.5 hours, 1 and 7 days after the interventions. Secondary outcome measures included subjective effects, tolerability, and biochemical assessments. RESULTS: Significant reductions (all P values <0.05) only in reaction times were observed in the 2 tasks in both groups, without between-group differences. Furthermore, significant reductions in anxiety, sedation, cognitive deterioration, and discomfort were observed in both groups, without between-group differences. Ayahuasca, with or without CBD, was well tolerated, producing mainly nausea and gastrointestinal discomfort. No clinically significant effects were observed on cardiovascular measurements and liver enzymes. CONCLUSIONS: There was no evidence of interactive effects between ayahuasca and CBD. The safety of separate and concomitant drug intake suggests that both drugs could be applied to clinical populations with anxiety disorders and in further trials with larger samples to confirm findings.

Hallucinations and Hallucinogens: Psychopathology or Wisdom?

Hallucinations are currently associated almost exclusively with psychopathological states. While it is evident that hallucinations can indicate psychopathology or neurological disorders, we should remember that hallucinations also commonly occur in people without any signs of psychopathology. A similar case occurs in the case of hallucinogenic drugs, which have been long associated with psychopathology and insanity. However, during the last decades a huge body of research has shown that certain kinds of hallucinations, exerted by hallucinogenic drugs, may serve to improve mental health. We propose that, in light of historical, epidemiological, and scientific research, hallucinations can be better characterized as a common phenomenon associated sometimes with psychopathology but also with functional and even beneficial outcomes. In the last sections of the manuscript, we extend our argument, suggesting that hallucinations can offer a via regia to knowledge of the mind and the world. This radical shift in the cultural interpretation of hallucinations could have several implications for fields such as drug policy, civil law, and psychiatry, as well as for the stigma associated with mental disorders.

The Kappa Opioid Receptor and the Sleep of Reason: Cortico-Subcortical Imbalance Following Salvinorin-A.

BACKGROUND: The mechanisms through which kappa opioid receptor (KOR) agonists induce psychotomimetic effects are largely unknown, although the modulation of this receptor has attracted attention for its clinical use. In this work, we characterize the neuropharmacological effects of salvinorin-A, a highly selective KOR agonist. METHODS: Changes in multimodal electroencephalography, single-photon emission computed tomography, and subjective effects following the acute administration of salvinorin-A are reported. The study included 2 sub-studies that employed a double-blind, crossover, randomized, placebo-controlled design. RESULTS: The electroencephalography measures showed a marked increase in delta and gamma waves and a decrease in alpha waves while subjects were under the effect of salvinorin-A. Regarding single-photon emission computed tomography measures, significant decreases in regional cerebral blood flow were detected in multiple regions of the frontal, temporal, parietal, and occipital cortices. Significant regional cerebral blood flow increases were observed in some regions of the medial temporal lobe, including the amygdala, the hippocampal gyrus, and the cerebellum. The pattern of subjective effects induced by salvinorin-A was similar to those observed in relation to other psychotomimetic drugs but with an evidently dissociative nature. No dysphoric effects were reported. CONCLUSION: The salvinorin-A-mediated KOR agonism induced dramatic psychotomimetic effects along with a generalized decrease in cerebral blood flow and electric activity within the cerebral cortex.

Effects of ayahuasca on the endocannabinoid system of healthy volunteers and in volunteers with social anxiety disorder: Results from two pilot, proof-of-concept, randomized, placebo-controlled trials.

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.

Acute Psychological Adverse Reactions in First-Time Ritual Ayahuasca Users: A Prospective Case Series.

BACKGROUND: In recent decades, ritualistic use of ayahuasca has spread throughout the world. Retrospective studies have suggested a good psychological safety profile, but prospective studies involving ceremony ayahuasca-naive participants are lacking. METHODS: We conducted the study using a subsample from a previous study, for which first-time ceremony ayahuasca participants were recruited. The subsample consisted of 7 subjects who experienced acute and challenging psychological reactions. The semistructured Mini-International Neuropsychiatric Interview and psychometric questionnaires were administered before participants attended the ayahuasca ceremony and at 1 and 6 months after exposure. Subjective experiences were also recorded. RESULTS: Seven subjects from a sample of 40 reported having experienced intense challenging psychological effects during the ayahuasca ceremony. Four of those 7 subjects met the diagnostic criteria for 1 or more psychiatric disorder before the ayahuasca ceremony. One month after the ceremony, 2 of those subjects no longer showed psychiatric symptoms, whereas the symptoms of the other 2 were reduced considerably. Those results persisted at the 6-month follow-up. Inappropriate setting/context (poor guiding skills and screening) contributed to some of the challenging reactions. Most of the participants (6 of 7) did not take ayahuasca again during the study period. CONCLUSIONS: Based on the cases reported here, we suggest that although it is possible that participating in ayahuasca ceremonies may entail acute psychological negative reactions, those challenging experiences can also have positive long-term effects. Prospective research on the safety profile of ayahuasca and how it is affected by the context of different practices and safety strategies is therefore necessary.

Psychedelic Medicines in Major Depression: Progress and Future Challenges.

The volume of research on the therapeutic use of psychedelic drugs has been increasing during the last decades. Partly because of the need of innovative treatments in psychiatry, several studies have assessed the safety and efficacy of drugs like psilocybin or ayahuasca for a wide range of mental disorders, including major depression. The first section of this chapter will offer an introduction to psychedelic research, including a brief historical overview and discussions about appropriate terminology. In the second section, the recently published clinical trials in which psychedelic drugs were administered to patients will be analysed in detail. Then, in the third section, the main neurobiological mechanisms of these drugs will be described, noting that while some of these mechanisms could be potentially associated with their therapeutic properties, they are commonly used as adjuvants in psychotherapeutic processes. The last section suggests future challenges for this groundbreaking field of research and therapy.

Quality of Life, Mental Health, Personality and Patterns of Use in Self-Medicated Cannabis Users with Chronic Diseases: A 12-Month Longitudinal Study.

The number of patients using cannabis for therapeutic purposes is growing worldwide. While research regarding the treatment of certain diseases/disorders with cannabis and cannabinoids is also expanding, only a few longitudinal studies have assessed the mid-term impacts of medical cannabis use on psychological variables and quality of life (QoL). The aim of the study was to assess the psychological safety and QoL of patients with chronic diseases who self-medicate with cannabis over time. We recruited patients with various chronic diseases who use cannabis and collected data regarding patterns of cannabis use as well as mental health, personality and QoL. Participants were followed-up at baseline, 4, 8 and 12 months. Hair analysis was conducted to confirm the presence of cannabinoids. Personality assessment showed a consistent decrease in self-transcendence and self-directedness scores. Neither cognitive nor psychopathological deterioration was found. There were also no variations in QoL. Mid-term use of medical cannabis seems to show adequate tolerability regarding cognitive and psychopathological abilities, and it may help patients with chronic diseases to maintain an acceptable QoL.

Cannabis and Public Health: A Study Assessing Regular Cannabis Users Through Health Indicators.

Background and Objective: An increasing number of countries are deciding to regulate the medicinal and/or recreational use of cannabis (Cannabis sativa L.). However, there is a lack of information on the impact of regular consumption of this substance on public health. In this study, for the first time, regular cannabis consumers in Spain were assessed using health indicators, comparing these data with the general population. Methods: Various items of the Enquesta de Salut de Catalunya (ESCA) and other items related to cannabis use were selected to build a survey and administer it to a representative sample of regular cannabis users in Catalonia. Results: Most of the indicators did not show any deterioration in the health of regular cannabis users compared with the general population. It was observed that users suffered from more sleep problems and about 40% of the sample would like to discontinue cannabis use, suggesting a dependence pattern. About 30% of the sample was able to discontinue the use of prescription medications because of cannabis. Social support and sleep problems, and not cannabis use, were predictors of depression and well-being scores. Conclusions: It seems that regular cannabis use, despite contributing to problems related to sleep quality or dependence, does not have a negative impact on public health in a manner detectable using health indicators.

A transcriptomic analysis in mice following a single dose of ibogaine identifies new potential therapeutic targets.

Ibogaine (IBO) is an atypical psychedelic with a complex mechanism of action. To date, the mechanisms that may underlie its anti-addictive effects are still not defined. This study aims to identify changes in gene expression induced by a single oral dose of IBO in the cortex of mice by means of a transcriptomic analysis for the first time. Our results showed significant alterations in gene expression in mouse frontal cortex samples 4 h after a single oral dose of IBO. Specifically, genes involved in hormonal pathways and synaptogenesis exhibited upregulation, while genes associated with apoptotic processes and endosomal transports showed downregulation. The findings were further corroborated through quantitative polymerase chain reaction (qPCR) analysis. However, the validation of gene expression related to hormonal pathways did not entirely align with the transcriptomic analysis results, possibly due to the brain region from which tissue was collected. Sex differences were observed, with female mice displaying more pronounced alterations in gene expression after IBO treatment. High variability was observed across individual animals. However, this study represents a significant advancement in comprehending IBO's molecular actions. The findings highlight the influence of IBO on gene expression, particularly on hormonal pathways, synaptogenesis, apoptotic processes, and endosomal transports. The identification of sex differences underscores the importance of considering sex as a potential factor influencing IBO's effects. Further research to assess different time points after IBO exposure is warranted.

Do classic psychedelics increase the risk of seizures? A scoping review.

Seizures are a concerning adverse event frequently associated with the use of psychedelics, and hence, studies involving these substances tend to exclude patients with past history of epilepsy. This is especially relevant because epileptic seizures are markedly increased in the population suffering from mental disorders, and psychedelic assisted therapy is being researched as a promising treatment for several of them. To determine the extent of the current literature on the relationship between classic psychedelics and seizures, a scoping review was performed using the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews). The search was conducted in PubMed, Web of Science, Google scholar, LILACS and Scielo, and both animal and human models were included. A total of 16 publications on humans, and 11 on animals, were found. The results are heterogeneous, but globally suggest that psychedelics may not increase the risk of seizures in healthy individuals or animals in the absence of other drugs. However, concomitant use of other substances or drugs, such as kambo or lithium, could increase the risk of seizures. Additionally, these conclusions are drawn from data lacking sufficient external validity, so they should be interpreted with caution. Future paths for research and a summary on possible neurobiological underpinnings that might clarify the relationship between classical psychedelics and seizures are also provided.

Validation of the Spanish version of the multifaceted empathy test: comparison between cannabis use effects and controls in social cognition.

OBJECTIVE: While social cognition is shown to be impaired in several mental disorders, the effects of cannabis on social cognition are still not clear. Past studies have used the multifaceted empathy test (MET) to study social cognition. This study aims to test the validity of the MET Spanish version and to evaluate the effects of cannabis use on social cognition. METHODS: In total 116 participants from a Cannabis Social Club (CSC) completed the MET and the reading the mind in the eyes test (RMET) under the effects of cannabis and were compared to 86 university students (control group). Internal consistency and convergent validity were assessed. Cognitive empathy (CE) and emotional empathy (EE) were tested in both groups. RESULTS: The MET CE scale shows low internal consistency, while the EE scale shows high internal consistency. Items showed similar difficulty for both groups. Cannabis users showed deficient overall emotional recognition, with reduced scores associated with positive stimuli. Overall scores for EE were similar for both groups, but the experimental group scored lower with negative stimuli when compared to controls. CONCLUSION: This study validates the MET Spanish version for its use in future studies. Results confirmed deficient emotional recognition in cannabis users and a dampened reaction to negative stimuli for the first time.

The modern clinical use of hallucinogens. What can we learn from the natural product research?

Can the emerging field of psychedelic research benefit from natural product research? We believe it can. In this manuscript we delineate certain topics of research with hallucinogens that directly connect with research on natural products in general.

Spanish versions and validation of a series of rating scales and visual analogue scales to assess the subjective effects of cannabis.

Cannabis is being legalized for medical and recreational purposes all around the world. However, the understanding of the psychological effects of cannabis is still limited, and it has been previously linked to mental disorders such as schizophrenia. Lately, new scales have been created and adapted to measure its psychological effects. The aim of this study is to create Spanish versions of some of these scales and test their psychometric characteristics. One hundred sixteen participants were recruited from Cannabis Social Clubs (CSC) in Barcelona, Spain. Participants under the effects of their own cannabis completed the Cannabis Experience Questionnaire-modified version (CEQ-mv), Addiction Research Centre Inventory-18 (ARCI-18), Psychotomimetic States Inventory (PSI) and Visual Analogue Scales (VAS). Questionnaires were completed in the CSC, providing a naturalistic setting for the study. Exploratory factor analysis and internal consistency were analyzed. PSI was reduced from a 6-factor to a 4-factor model with adequate to low reliability, ARCI-18 was reduced from a 3-factor to a 2-factor model with good reliability, and VAS were reduced from a 4-factor to a 3-factor model, also with good reliability. These questionnaires showed adequate reliability and can be used in future studies to test the subjective effects of cannabis in clinical and naturalistic settings.

Underground ibogaine use for the treatment of substance use disorders: A qualitative analysis of subjective experiences.

INTRODUCTION: Ibogaine is one of the alkaloids naturally found in plants such as Tabernanthe iboga, which has been traditionally used by members of the Bwiti culture. Since the discovery of its anti-addictive properties by Howard S. Lotsof in 1962, ibogaine has been used experimentally to treat substance use disorders (SUD), especially those involving opioids. We aim to provide a detailed understanding of the underlying psychological aspects of underground ibogaine use for the treatment of SUD. METHODS: Semi-structured interviews were carried out with 13 participants with SUD, which motivated their self-treatment with ibogaine. The data were analysed using the grounded theory approach and considered the context of the treatment, and the nature of the occurring hallucinogenic and cognitive phenomena during the treatment experience. RESULTS: We identified several psychological effects that the study respondents experienced, which seem to play a substantial role in the therapeutic process concerning SUD. The evoking of interpersonal and transpersonal experiences, autobiographical memories, and preparation, integration and motivation for a lifestyle change are important components that participants reported during and after ibogaine intake. DISCUSSION AND CONCLUSION: Ibogaine is increasingly being used for the treatment of SUD, due in part to the limited treatment options currently available. Its beneficial effects seem to be related not only to its complex pharmacology but also to the subjective experience that ibogaine induces. The main aspects of this experience are related to autobiographical memories and valuable personal insights, which together appear to help individuals cope with their SUD.

Main targets of ibogaine and noribogaine associated with its putative anti-addictive effects: A mechanistic overview.

BACKGROUND: There is a growing interest in studying ibogaine (IBO) as a potential treatment for substance use disorders (SUDs). However, its clinical use has been hindered for mainly two reasons: First, the lack of randomized, controlled studies informing about its safety and efficacy. And second, IBO's mechanisms of action remain obscure. It has been challenging to elucidate a predominant mechanism of action responsible for its anti-addictive effects. OBJECTIVE: To describe the main targets of IBO and its main metabolite, noribogaine (NOR), in relation to their putative anti-addictive effects, reviewing the updated literature available. METHODS: A comprehensive search involving MEDLINE and Google Scholar was undertaken, selecting papers published until July 2022. The inclusion criteria were both theoretical and experimental studies about the pharmacology of IBO. Additional publications were identified in the references of the initial papers. RESULTS: IBO and its main metabolite, NOR, can modulate several targets associated with SUDs. Instead of identifying key targets, the action of IBO should be understood as a complex modulation of multiple receptor systems, leading to potential synergies. The elucidation of IBO's pharmacology could be enhanced through the application of methodologies rooted in the polypharmacology paradigm. Such approaches possess the capability to describe multifaceted patterns within multi-target drugs. CONCLUSION: IBO displays complex effects through multiple targets. The information detailed here should guide future research on both mechanistic and therapeutic studies.

Ayahuasca and Public Health II: Health Status in a Large Sample of Ayahuasca-Ceremony Participants in the Netherlands.

Ayahuasca is a plant decoction in traditional Amazonian medicine. Its ritual use has been internationalized, leading to policy challenges that countries should address. This study evaluates the impact of regular ayahuasca ceremony participation on health by assessing the health status of 377 participants in ayahuasca ceremonies in the Netherlands using validated health indicators. A questionnaire was developed and administered to study participants. The questionnaire included several health indicators with public health relevance (e.g., BMI, diet, physical activity) and psychometrically validated questionnaires (ELS and COPE-easy). The data retrieved through health indicators was compared to normative Dutch data. Participants (50.1% women) were mostly Dutch (84.6%) with a mean age of 48.8 years (SD = 11.6). Compared to normative Dutch data, regular participants in ayahuasca ceremonies showed better general well-being, fewer chronic or lifestyle-related diseases, more physical activity, and a more balanced diet. Participants also used less alcohol during the COVID-19 pandemic, and although they used more illegal drugs than the general population, they did not report associated harms. Our findings suggest that regular participation in ayahuasca ceremonies is not linked to relevant health harms. This data could help drug policymakers to develop and implement evidence-based public policies.

Ayahuasca-induced personal death experiences: prevalence, characteristics, and impact on attitudes toward death, life, and the environment.

Introduction: Despite an emerging understanding regarding the pivotal mechanistic role of subjective experiences that unfold during acute psychedelic states, very little has been done in the direction of better characterizing such experiences and determining their long-term impact. The present paper utilizes two cross-sectional studies for spotlighting - for the first time in the literature - the characteristics and outcomes of self-reported past experiences related to one's subjective sense of death during ayahuasca ceremonies, termed here Ayahuasca-induced Personal Death (APD) experiences. Methods: Study 1 (n = 54) reports the prevalence, demographics, intensity, and impact of APDs on attitudes toward death, explores whether APDs are related with psychopathology, and reveals their impact on environmental concerns. Study 2 is a larger study (n = 306) aiming at generalizing the basic study 1 results regarding APD experience, and in addition, examining whether APDs is associated with self-reported coping strategies and values in life. Results: Our results indicate that APDs occur to more than half of those participating in ayahuasca ceremonies, typically manifest as strong and transformative experiences, and are associated with an increased sense of transcending death (study 1), as well as the certainty in the continuation of consciousness after death (study 2). No associations were found between having undergone APD experiences and participants' demographics, personality type, and psychopathology. However, APDs were associated with increased self-reported environmental concern (study 1). These experiences also impact life in profound ways. APDs were found to be associated with increases in one's self-reported ability to cope with distress-causing life problems and the sense of fulfillment in life (study 2). Discussion: The study's findings highlight the prevalence, safety and potency of death experiences that occur during ayahuasca ceremonies, marking them as possible mechanisms for psychedelics' long-term salutatory effects in non-clinical populations. Thus, the present results join other efforts of tracking and characterizing the profound subjective experiences that occur during acute psychedelic states.

Longitudinal and transcultural assessment of the relationship between hallucinogens, well-being, and post-traumatic growth during the COVID-19 pandemic.

The COVID-19 pandemic has had a devastating impact on the health and wellbeing of the global population. This paper presents the results of a longitudinal transcultural study that was begun at the peak of the pandemic (in April, 2020). An online survey was used to collect data from English-, Spanish-, and Portuguese-speaking participants. The survey collected information about sociodemographics, lifestyle activities, COVID-19-related circumstances, and drug use (with an emphasis on hallucinogenic drugs), as well as involving psychometric questionnaires. Users of hallucinogenic drugs had higher psychological well-being and lower scores on psychopathology scales, both at baseline and during follow-ups. This difference was larger when users were distinguished by frequency of use, as regular users scored higher on psychological well-being and lower on psychopathology scales. Subjects with more psychological distress had lower scores for all scales of post-traumatic growth, but if they were regular hallucinogens users, they had higher scores for post-traumatic growth. When comparing the results between cultural contexts, heterogeneous results were obtained. There were more English-speaking regular users of hallucinogenic drugs. Further research should analyse the potential role of hallucinogens in large-scale catastrophes, with a special focus on post-traumatic growth.

Communalistic use of psychoactive plants as a bridge between traditional healing practices and Western medicine: A new path for the Global Mental Health movement.

The Global Mental Health (GMH) movement aims to provide urgently needed treatment to those with mental illness, especially in low- and middle-income countries. Due to the complexity of providing mental health services to people from various cultures, there is much debate among GMH advocates regarding the best way to proceed. While biomedical interventions offer some degree of help, complementary approaches should focus on the social/community aspects. Many cultures conduct traditional rituals involving the communal use of psychoactive plants. We propose that these practices should be respected, protected, and promoted as valuable tools with regard to mental health care at the community level. The traditional use of psychoactive plants promotes community engagement and participation, and they are relatively affordable. Furthermore, the worldviews and meaning-making systems of local population are respected. The medical systems surrounding the use of psychoactive plants can be explained in biomedical terms, and many recently published clinical trials have demonstrated their therapeutic potential. Psychoactive plants and associated rituals offer potential benefits as complementary aspects of mental health services. They should be considered as such by international practitioners and advocates of the GMH movement.

The Use of Cannabis sativa L. for Pest Control: From the Ethnobotanical Knowledge to a Systematic Review of Experimental Studies.

Background: Despite the benefits that synthetic pesticides have provided in terms of pest and disease control, they cause serious long-term consequences for both the environment and living organisms. Interest in eco-friendly products has subsequently increased in recent years. Methods: This article briefly analyzes the available ethnobotanical evidence regarding the use of Cannabis sativa as a pesticide and offers a systematic review of experimental studies. Results: Our findings indicate that both ethnobotanical and experimental procedures support the use of C. sativa as a pesticide, as remarkable toxicity has been observed against pest organisms. The results included in the systematic review of experimental studies (n=30) show a high degree of heterogeneity, but certain conclusions can be extracted to guide further research. For instance, promising pesticide properties were reported for most of the groups of species tested, especially Arachnida and Insecta; the efficacy of C. sativa as a pesticide can be derived from a wide variety of compounds that it contains and possible synergistic effects; it is crucial to standardize the phytochemical profile of C. sativa plants used as well as to obtain easily reproducible results; appropriate extraction methods should be explored; and upper inflorescences of the plant may be preferred for the production of the essential oil, but further studies should explore better other parts of the plant. Conclusion: In the coming years, as new findings are produced, the promising potential of C. sativa as a pesticide will be elucidated, and reviews such as the present one constitute useful basic tools to make these processes easier.