The biosynthetic pathway of the hallucinogen mescaline and its heterologous reconstruction.

Mescaline, among the earliest identified natural hallucinogens, holds great potential in psychotherapy treatment. Nonetheless, despite the existence of a postulated biosynthetic pathway for more than half a century, the specific enzymes involved in this process are yet to be identified. In this study, we investigated the cactus Lophophora williamsii (Peyote), the largest known natural producer of the phenethylamine mescaline. We employed a multi-faceted approach, combining de novo whole-genome and transcriptome sequencing with comprehensive chemical profiling, enzymatic assays, molecular modeling, and pathway engineering for pathway elucidation. We identified four groups of enzymes responsible for the six catalytic steps in the mescaline biosynthetic pathway, and an N-methyltransferase enzyme that N-methylates all phenethylamine intermediates, likely modulating mescaline levels in Peyote. Finally, we reconstructed the mescaline biosynthetic pathway in both Nicotiana benthamiana plants and yeast cells, providing novel insights into several challenges hindering complete heterologous mescaline production. Taken together, our study opens up avenues for exploration of sustainable production approaches and responsible utilization of mescaline, safeguarding this valuable natural resource for future generations.

Scoping Review: The Role of Psychedelics in the Management of Chronic Pain.

Introduction: Amid a lack of effective chronic pain treatments, psychedelics have gained attention as a potential solution, although their Schedule 1 classification poses challenges. Psychedelics, such as lysergic acid diethylamide (LSD) and psilocybin, have gained popularity as alternatives and adjuncts for chronic pain treatment. Studies suggest that they may modulate pain processing through agonism primarily at the serotonin receptor, 5-HT2A. One of the first of its nature, we present an artificial intelligence (AI)-powered scoping review primarily focusing on evaluating psychedelics for chronic pain conditions such as cluster headache, phantom limb pain, and fibromyalgia. Methods: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, we used an AI-powered comprehensive search strategy utilizing the ChatGPT4.0 Bing chat to search Medline, Embase, Cochrane, and Google Scholar for articles addressing chronic pain. The query was performed on June 1, 2023, focusing on psychedelics for chronic, non-cancer pain including headache disorders. Inclusion criteria were English-only, peer-reviewed articles involving human participants >18 years, focusing on chronic pain conditions (eg, phantom limb pain and cluster headache), using LSD, 2.5-dimethoxy-4-bromophenethylamine (2C-B), N, N-dimethyltryptamine (DMT), psilocybin, or mescaline. Exclusion criteria were reviews, editorials, and opinion articles and studies focusing on tetrahydrocannabinol/cannabis and/or ketamine. Results: A total of 186 unique database entries were retrieved, of which nine studies were included in the scoping review. These included four case reports/series, an open-label study, a cohort study, two online surveys, and a randomized, double-blind, placebo-controlled trial. They comprised three studies addressing phantom limb pain, four addressing cluster headaches, and two addressing fibromyalgia, spinal cord injury, complex regional pain syndrome, and lumbar radiculopathy. Conclusion: Psychedelics may have potential in alleviating pain symptoms secondary to a multitude of chronic pain conditions. However, further randomized, double-blind, placebo-controlled trials are needed to further explore and evaluate the role of psychedelics in chronic, non-cancer pain.

An Overview on the Hallucinogenic Peyote and Its Alkaloid Mescaline: The Importance of Context, Ceremony and Culture.

Peyote (Lophophora williamsii) is a cactus that contains various biologically active alkaloids-such as pellotine, anhalonidine, hordenine and mescaline. Here, mescaline induces the psychoactive effects of peyote through the activation of the serotonin 5-HT2A receptor and the subsequent release of calcium (Ca2+) from the endoplasmic reticulum (ER). Moreover, an evaluation of the therapeutic benefits of mescaline is also currently the subject of research. It is important to consider that the outcome of taking a psychedelic drug strongly depends on the mindset of the recipient and the context (set and setting principle), including ceremonies and culture. This overview serves to summarise the current state of the knowledge of the metabolism, mechanism of action and clinical application studies of peyote and mescaline. Furthermore, the benefits of the potential of peyote and mescaline are presented in a new light, setting an example for combining a form of treatment embedded in nature and ritually enriched with our current highly innovative Western medicine.

Cardiac effects of ephedrine, norephedrine, mescaline, and 3,4-methylenedioxymethamphetamine (MDMA) in mouse and human atrial preparations.

The use of recreational drugs like ephedrine, norephedrine, 3,4-methylenedioxymethamphetamine (MDMA), and mescaline can lead to intoxication and, at worst, to death. One reason for a fatal course of intoxication with these drugs might lie in cardiac arrhythmias. To the best of our knowledge, their inotropic effects have not yet been studied in isolated human cardiac preparations. Therefore, we measured inotropic effects of the hallucinogenic drugs ephedrine, norephedrine, mescaline, and MDMA in isolated mouse left atrial (mLA) and right atrial (mRA) preparations as well as in human right atrial (hRA) preparations obtained during cardiac surgery. Under these experimental conditions, ephedrine, norephedrine, and MDMA increased force of contraction (mLA, hRA) and beating rate (mRA) in a time- and concentration-dependent way, starting at 1-3 µM but these drugs were less effective than isoprenaline. Mescaline alone or in the presence of phosphodiesterase inhibitors did not increase force in mLA or hRA. The positive inotropic effects of ephedrine, norephedrine, or MDMA were accompanied by increases in the rate of tension and relaxation and by shortening of time of relaxation and, moreover, by an augmented phosphorylation state of the inhibitory subunit of troponin in hRA. All effects were greatly attenuated by cocaine (10 µM) or propranolol (10 µM) treatment. In summary, the hallucinogenic drugs ephedrine, norephedrine, and MDMA, but not mescaline, increased force of contraction and increased protein phosphorylation presumably, in part, by a release of noradrenaline in isolated human atrial preparations and thus can be regarded as indirect sympathomimetic drugs in the human atrium.

The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Report: Serotonergic Psychedelic Treatments for Major Depressive Disorder.

OBJECTIVE: Serotonergic psychedelics are re-emerging as potential novel treatments for several psychiatric disorders including major depressive disorder. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence and provide a consensus recommendation for the clinical use of psychedelic treatments for major depressive disorder. METHODS: A systematic review was conducted to identify contemporary clinical trials of serotonergic psychedelics for the treatment of major depressive disorder and cancer-related depression. Studies published between January 1990 and July 2021 were identified using combinations of search terms, inspection of bibliographies and review of other psychedelic reviews and consensus statements. The levels of evidence for efficacy were graded according to the Canadian Network for Mood and Anxiety Treatments criteria. RESULTS: Only psilocybin and ayahuasca have contemporary clinical trials evaluating antidepressant effects. Two pilot studies showed preliminary positive effects of single-dose ayahuasca for treatment-resistant depression (Level 3 evidence). Small randomized controlled trials of psilocybin combined with psychotherapy showed superiority to waitlist controls and comparable efficacy and safety to an active comparator (escitalopram with supportive psychotherapy) in major depressive disorder, with additional randomized controlled trials showing efficacy specifically in cancer-related depression (Level 3 evidence). There was only one open-label trial of psilocybin in treatment-resistant unipolar depression (Level 4 evidence). Small sample sizes and functional unblinding were major limitations in all studies. Adverse events associated with psychedelics, including psychological (e.g., psychotomimetic effects) and physical (e.g., nausea, emesis and headaches) effects, were generally transient. CONCLUSIONS: There is currently only low-level evidence to support the efficacy and safety of psychedelics for major depressive disorder. In Canada, as of 2022, psilocybin remains an experimental option that is only available through clinical trials or the special access program. As such, Canadian Network for Mood and Anxiety Treatments considers psilocybin an experimental treatment and recommends its use primarily within clinical trials, or, less commonly, through the special access program in rare, special circumstances.

Exploración del efecto de Trichocereus pachanoi en el carácter depresivo en ratas / Exploring the effect of Trichocereus pachanoi on the depression-like behavior in rats

Introducción: Existen plantas que se usan desde tiempos ancestrales con efecto alucinógeno y alteraciones al sistema nervioso central, debido a la presencia principalmente de mezcalina son usadas para cumplir objetivos tradicionales asociados a la adivinación, curandería, divinidad y otros. Objetivos: Determinar el efecto del extracto acuoso de Trichocereus pachanoi a dosis de 10 por ciento, 20 por ciento y 30 por ciento sobre el comportamiento exploratorio de carácter depresivo en Rattus rattus var. albinus. Material y métodos: El presente estudio experimental es de carácter exploratorio aplicado, constructivo y prospectivo, se formaron 4 grupos de 10 ratas cada uno a las que se les administró extracto acuoso de Trichocereus pachanoi en dosis creciente, luego fueron sometidas a natación forzada con entrenamiento previo de 15 minutos. Resultados: El grupo que no recibió tratamiento alguno posee la más baja respuesta en gasto de tiempo para el escalamiento, comparado con los grupos B, C y D que presentan 13,5 min. 17,17 min. y 24,37 min. respectivamente. También en la evaluación de la movilidad, el grupo A posee en valor más bajo, comparado con los grupos B, C y D que presentan 13,42 min. 17,62 min. y 23,12 min., respectivamente. Conclusiones: El tratamiento en ratas con extracto acuoso de Trichocereus pachanoi a concentraciones de 10 por ciento, 20 por ciento y 30 por ciento ha sido eficaz en producir un efecto tranquilizante en el comportamiento exploratorio de carácter depresivo en el sujeto(AU)

Introduction: Since ancient times, some mescaline containing plants that have hallucinogen effects and cause alterations in the central nervous system have been used to fulfill traditional objectives associated with divination, healing, spirituality and others. Objective: To determine the effect of the aqueous extract of Trichocereus pachanoi at doses of 10 %, 20 % and 30 % solution on depression-like exploratory behavior in Rattus rattus var. albinus. Material and Methods: The present experimental study, which is exploratory, constructive and prospective in nature, was conducted in 4 groups of 10 rats. The rats were administered increasing doses of aqueous extract of Trichocereus pachanoi; then, they underwent forced swimming with a previous 15-minute training. Results: The group that did not receive any treatment had the lowest response to the duration of time spent at scaling compared to groups B, C and D that spent 13.5 min., 17.17 min., and 24.37 min., respectively. Also, in the evaluation of mobility, group A showed the lowest value compared to groups B, C and D that recorded 13.42 min., 17.62 min., and 23.12 min., respectively. Conclusions: The treatment with aqueous extract of Trichocereus pachanoi at concentrations of 10 percent, 20 percent and 30 percent applied to rats has been effective in producing a tranquilizer effect on the depression-like exploratory behavior in rats(AU)

Bioactive compounds and health benefits of Pereskioideae and Cactoideae: A review.

Several genera of the Cactoideae and Pereskioideae subfamilies (Hylocereus, Cereus, Pilosocereus, Stenocereus, Myrtillocactus, Melocactus and Pereskia genera) are often consumed as fresh fruits, processed foods and as functional plants. This review discusses the complete bioactive composition related to the genetic effects, the health properties and the safety of these succulent plants, aiming to provide some contributions for future research. Their cladodes, leaves and fruits are notable for water-soluble compounds, carbohydrate polymers, bioactive nitrogen compounds, polyphenols and some uncommon terpenoids. Mucilage, phenethylamines, flavonol glycosides, betalains and some uncommon triterpenoids have been related to the improvement of human health against general inflammation, metabolic disorders and disturbances of the digestive system. The intensive study of different species (and accessions) of both subfamilies, including their complete chemical profile related to genetic and environmental effects, biological properties and safety could represent a significant contribution to benefit human health and preserve biodiversity.

Usos terapéuticos de sustancias prohibidas: LSD, MDMA, THC, GHB, DMT, psilocybina y mescalina / Therapeutic uses of prohibited substances: LSD, MDMA, THC, GHB, DMT, psilocybin, mescaline

El presente texto hace un breve recorrido sobre los usos terapéuticos que han tenido la LSD, MDMA, THC, GHB, DMT, Psilocybina y Mescalina en la historia, así como también refiere algunos de los beneficios para la salud física y mental que se considera tienen en la actualidad. Esta información científica se contrapone a la normativa internacional en materia de drogas, que las clasifica como sustancias prohibidas en la Lista I, debido a su falta de uso médico aceptado por Estados Unidos y a su alto potencial de abuso. En este trayecto también se intenta comprender a qué hace referencia dicho potencial, así como las motivaciones que podrían existir detrás de la prohibición del uso terapéutico de estas drogas. En este marco, se consideran consecuencias para la salud de la población, las que atentan contra los Derechos Humanos de las personas que podrían requerir alguna de estas sustancias.

This paper makes a brief of the therapeutic uses have had the LSD, MDMA, THC, GHB, DMT, Psilocybin and Mescaline in history, as well as some of the benefits referred to physical and mental health that are considered today. This scientific information seems contrary to international legislation on drugs, which classifies as prohibited substances in Schedule I, due to its lack of acceptance medical use by the United States and its high potential for abuse. In this way also try to understand what makes this potential reference, and the reasons that could be behind the ban on therapeutic use of these drugs. In this framework, we consider health consequences of the population, which violate the human rights of people who may require some of these substances.