Toward a More Sustainable Sample Preparation in Phytochemistry: Case Studies in Four Subclasses of Alkaloids.

The fact that alkaloids are bases has been the most explored chemical feature of their extraction and purification procedures. The main drawback of these procedures is that they employ undesirable chemicals, with HCl and CH2Cl2 probably being the most commonly employed chemicals in their subsequent steps. This work tested the hypothesis that advantages in recovery efficiency support this common practice. Experiments were conducted in three laboratories, monitoring the alkaloids harmine (1), boldine (2), vincamine (3), and mescaline (4) extracted from Banisteriopsis caapi, Peumus boldus, Vinca minor, and Trichocereus macrogonus var. pachanoi, respectively. The research demonstrated that HCl could be replaced with citric acid (CA) without loss or even better extraction performance. The recommended EtOAc could completely replace CH2Cl2 in three out of four study cases and partially in the fourth case without harming the extraction efficiency. In addition, the alternative solvents tert-amyl methyl ether (TAME) and n-butyl acetate (BuOAc) could enhance the extraction of alkaloids. These results might incentivize natural products laboratories to consider sustainability more routinely, thus being closer to current practices in the pharmaceutical industry, which has been replacing solvents and processes with greener ones.

Drug-drug interactions involving classic psychedelics: A systematic review.

Classic psychedelics, including lysergic acid diethylamide (LSD), psilocybin, mescaline, N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), are potent psychoactive substances that have been studied for their physiological and psychological effects. However, our understanding of the potential interactions and outcomes when using these substances in combination with other drugs is limited. This systematic review aims to provide a comprehensive overview of the current research on drug-drug interactions between classic psychedelics and other drugs in humans. We conducted a thorough literature search using multiple databases, including PubMed, PsycINFO, Web of Science and other sources to supplement our search for relevant studies. A total of 7102 records were screened, and studies involving human data describing potential interactions (as well as the lack thereof) between classic psychedelics and other drugs were included. In total, we identified 52 studies from 36 reports published before September 2, 2023, encompassing 32 studies on LSD, 10 on psilocybin, 4 on mescaline, 3 on DMT, 2 on 5-MeO-DMT and 1 on ayahuasca. These studies provide insights into the interactions between classic psychedelics and a range of drugs, including antidepressants, antipsychotics, anxiolytics, mood stabilisers, recreational drugs and others. The findings revealed various effects when psychedelics were combined with other drugs, including both attenuated and potentiated effects, as well as instances where no changes were observed. Except for a few case reports, no serious adverse drug events were described in the included studies. An in-depth discussion of the results is presented, along with an exploration of the potential molecular pathways that underlie the observed effects.

Set and setting predict psychopathology, wellbeing and meaningfulness of psychedelic experiences: a correlational study.

BACKGROUND: In psychedelic therapy, the importance of set and setting is a fundamental but under-researched assumption. The aim of this study is to correlate variables of set (psychedelic use motivation) and setting (psychedelic use location and type of companion) with psychopathology, wellbeing and personality variables. RESEARCH DESIGN AND METHODS: A sample of 1022 participants of the Spanish-speaking population was collected through an online survey. A novel instrument, the Psychedelic Use Scale (PUS), was developed to measure substance use variables of LSD, mescaline, psilocybin, DMT, 5-Meo-DMT, ketamine, Salvia divinorum, ibogaine and MDMA. Various personality, well-being and psychopathology instruments were implemented to measure outcome variables. RESULTS: Growth motivations, natural settings and presence of significant others predicted less psychopathology, greater wellbeing and meaningfulness of psychedelic experiences, whereas problematic motivations predicted greater psychopathology, lower wellbeing and did not predict meaningfulness of psychedelic experiences. CONCLUSIONS: Based on these results, we suggest experimental hypotheses for future clinical trials and longitudinal studies with potential clinical implications.

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.

Psychedelics for treatment resistant depression: are they game changers?

INTRODUCTION: A new era of treatment for adults with treatment-resistant depression (TRD), which involves psychedelic substances, is dawning. Emerging evidence indicates that psychedelics can exert antidepressant effects through multiple neurobiological and psychological mechanisms. However, it remains to be seen if these new treatments will revolutionize the treatment of TRD. AREAS COVERED: The present review focuses on the efficacy of serotoninergic psychedelics psilocybin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), ayahuasca, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and mescaline (3,4,5-trimethoxyphenethylamine), as well as 3,4-methylenedioxymethamphetamine (MDMA), for TRD. A systematic search was conducted for psilocybin in TRD as emerging trials had not yet been subject to review. A narrative review summarized findings on other psychedelics. EXPERT OPINION: Psychedelic therapy has created a paradigm shift in the treatment of TRD, as it can maximize therapeutic benefits and minimize potential risks. Psilocybin holds promise as a potential game-changer in the treatment of TRD, with initial evidence suggesting a rapid antidepressant effect sustained for some responders for at least 3 months. Nevertheless, further adequately powered, double-blind, comparator-controlled trials are required to explore and clarify the mechanisms of action and long-term effects of psychedelics in TRD. Psychedelics also hold promise for other psychiatric conditions, such as bipolar depression and post-traumatic stress disorder.

Cardiovascular safety of psychedelic medicine: current status and future directions.

Psychedelics are powerful psychoactive substances that alter perception and mood processes. Their effectiveness in the treatment of psychiatric diseases was known before their prohibition. An increasing number of recent studies, due to the indisputable resurgence of serotonergic hallucinogens, have shown their efficacy in alleviating depression, anxiety, substance abuse therapies, and existential distress treatment in patients facing life-threatening illness. Psychedelics are generally considered to be physiologically safe with low toxicity and low addictive potential. However, their agonism at serotonergic receptors should be considered in the context of possible serotonin-related cardiotoxicity (5-HT2A/2B and 5-HT4 receptors), influence on platelet aggregation (5-HT2A receptor), and their proarrhythmic potential. The use of psychedelics has also been associated with significant sympathomimetic effects in both experimental and clinical studies. Therefore, the present review aims to provide a critical discussion of the cardiovascular safety of psilocybin, d-lysergic acid diethylamide (LSD), N,N-dimethyltryptamine, ayahuasca, and mescaline, based on the results of experimental research and clinical trials in humans. Experimental studies provide inconsistent information on the potential cardiovascular effects and toxicity of psychedelics. Data from clinical trials point to the relative cardiovascular safety of psychedelic-assisted therapies in the population of "healthy" volunteers. However, there is insufficient evidence from therapies carried out with microdoses of psychedelics, and there is still a lack of data on the safety of psychedelics in the population of patients with cardiovascular disease. Therefore, the exact determination of the cardiovascular safety of psychedelic therapies (especially long-term therapies) requires further research.

Elucidation of the mescaline biosynthetic pathway in peyote (Lophophora williamsii).

Peyote (Lophophora williamsii) is an entheogenic and medicinal cactus native to the Chihuahuan desert. The psychoactive and hallucinogenic properties of peyote are principally attributed to the phenethylamine derivative mescaline. Despite the isolation of mescaline from peyote over 120 years ago, the biosynthetic pathway in the plant has remained undiscovered. Here, we use a transcriptomics and homology-guided gene discovery strategy to elucidate a near-complete biosynthetic pathway from l-tyrosine to mescaline. We identified a cytochrome P450 that catalyzes the 3-hydroxylation of l-tyrosine to l-DOPA, a tyrosine/DOPA decarboxylase yielding dopamine, and four substrate-specific and regiospecific substituted phenethylamine O-methyltransferases. Biochemical assays with recombinant enzymes or functional analyses performed by feeding putative precursors to engineered yeast (Saccharomyces cerevisiae) strains expressing candidate peyote biosynthetic genes were used to determine substrate specificity, which served as the basis for pathway elucidation. Additionally, an N-methyltransferase displaying broad substrate specificity and leading to the production of N-methylated phenethylamine derivatives was identified, which could also function as an early step in the biosynthesis of tetrahydroisoquinoline alkaloids in peyote.

The risk of chronic psychedelic and MDMA microdosing for valvular heart disease.

Psychedelic microdosing is the practice of taking very low doses of psychedelic substances, typically over a longer period of time. The long-term safety of chronic microdosing is relatively uncharacterized, but valvular heart disease (VHD) has been proposed as a potential risk due to activation of the serotonin 5-HT2B receptor. However, this risk has not yet been comprehensively assessed. This analysis searched for all relevant in vitro, animal, and clinical studies related to the VHD risk of lysergic acid diethylamide (LSD), psilocybin, mescaline, N,N-dimethyltryptamine (DMT), and the non-psychedelic 3,4-methylenedioxymethamphetamine (MDMA). All five compounds and some metabolites could bind to the 5-HT2B receptor with potency equal to or greater than that of the 5-HT2A receptor, the primary target of psychedelics. All compounds were partial agonists at the 5-HT2B receptor with the exception of mescaline, which could not be adequately assessed due to low potency. Safety margins relative to the maximum plasma concentrations from typical microdoses were greater than known valvulopathogens, but not without potential risk. No animal or clinical studies appropriately designed to evaluate VHD risk were found for the four psychedelics. However, there is some clinical evidence that chronic ingestion of full doses of MDMA is associated with VHD. We conclude that VHD is a potential risk with chronic psychedelic microdosing, but further studies are necessary to better define this risk.

The Resurgence of Hallucinogen Drugs in Clinical Research.

Since the dawn of civilization, ancient cultures have utilized hallucinogens from plants and fungi in the context of religious and healing practices. Recently, their use has expanded to other cultures. Hallucinogens are natural or synthetic substances that alter the perception of reality at nontoxic doses, producing intense psychological and physiological effects. The initial research on hallucinogens began in the 1950s. However, their non-medical use, studies without proper controls, and negative social opinion resulted in legal restrictions that limited their use for clinical and preclinical research for more than two decades. A renewed interest in studying hallucinogens as potential therapeutic agents for treating different psychiatric conditions has recently re-emerged. This review summarizes the effects of main hallucinogen drugs and their therapeutic potential. Classic hallucinogens such as LSD, dimethyltryptamine, psilocin, and mescaline have chemical structures similar to serotonin and directly activate 5-hydroxy-tryptamine (5-HT2A) receptors. Ketamine is a dissociative anesthetic with antagonist effects at the glutamatergic N-methyl-D-aspartate receptor, indirectly activating 5-HT2A receptors. Ketamine has rapid antidepressant effects and reduces suicidal ideation, but its effects are short-lasting. Other hallucinogens are under study. It is necessary to continue this research with a more rigorous methodology and include studying the long-term effects of psychedelics use.

Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants.

Mescaline, lysergic acid diethylamide (LSD), and psilocybin are classic serotonergic psychedelics. A valid, direct comparison of the effects of these substances is lacking. The main goal of the present study was to investigate potential pharmacological, physiological and phenomenological differences at psychoactive-equivalent doses of mescaline, LSD, and psilocybin. The present study used a randomized, double-blind, placebo-controlled, cross-over design to compare the acute subjective effects, autonomic effects, and pharmacokinetics of typically used, moderate to high doses of mescaline (300 and 500 mg), LSD (100 µg), and psilocybin (20 mg) in 32 healthy participants. A mescaline dose of 300 mg was used in the first 16 participants and 500 mg was used in the subsequent 16 participants. Acute subjective effects of 500 mg mescaline, LSD, and psilocybin were comparable across various psychometric scales. Autonomic effects of 500 mg mescaline, LSD, and psilocybin were moderate, with psilocybin causing a higher increase in diastolic blood pressure compared with LSD, and LSD showing a trend toward an increase in heart rate compared with psilocybin. The tolerability of mescaline, LSD, and psilocybin was comparable, with mescaline at both doses inducing slightly more subacute adverse effects (12-24 h) than LSD and psilocybin. Clear distinctions were seen in the duration of action between the three substances. Mescaline had the longest effect duration (mean: 11.1 h), followed by LSD (mean: 8.2 h), and psilocybin (mean: 4.9 h). Plasma elimination half-lives of mescaline and LSD were similar (approximately 3.5 h). The longer effect duration of mescaline compared with LSD was due to the longer time to reach maximal plasma concentrations and related peak effects. Mescaline and LSD, but not psilocybin, enhanced circulating oxytocin. None of the substances altered plasma brain-derived neurotrophic factor concentrations. In conclusion, the present study found no evidence of qualitative differences in altered states of consciousness that were induced by equally strong doses of mescaline, LSD, and psilocybin. The results indicate that any differences in the pharmacological profiles of mescaline, LSD, and psilocybin do not translate into relevant differences in the subjective experience. ClinicalTrials.gov identifier: NCT04227756.

Examining associations between MDMA/ecstasy and classic psychedelic use and impairments in social functioning in a U.S. adult sample.

Impairment in social functioning is a common source of morbidity across many mental health disorders, yet there is a dearth of effective and easily implemented interventions to support social functioning. MDMA/ecstasy and classic psychedelics (psilocybin, LSD, peyote, mescaline) represent two potential treatments for impairments in social functioning, as evidence suggests these compounds may be supportive for alleviating social difficulties. Using a nationally representative sample of U.S. adults from the National Survey on Drug Use and Health (2015-2019) (N = 214,505), we used survey-weighted multivariable ordinal and logistic regression to examine the associations between lifetime use of the aforementioned compounds and impairments in social functioning in the past year. Lifetime MDMA/ecstasy use was associated with lowered odds of three of our four social impairment outcomes: difficulty dealing with strangers (aOR 0.92), difficulty participating in social activities (aOR 0.90), and being prevented from participating in social activities (aOR 0.84). Lifetime mescaline use was also associated with lowered odds of difficulty dealing with strangers (aOR 0.85). All other substances either shared no relationship with impairments in social functioning or conferred increased odds of our outcomes. Future experimental studies can assess whether these relationships are causal.

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.

Among psychedelic-experienced users, only past use of psilocybin reliably predicts nature relatedness.

BACKGROUND: Past research reports a positive relationship between experience with classic serotonergic psychedelics and nature relatedness (NR). However, these studies typically do not distinguish between different psychedelic compounds, which have a unique psychopharmacology and may be used in specific contexts and with different intentions. Likewise, it is not clear whether these findings can be attributed to substance use per se or unrelated variables that differentiate psychedelic users from nonusers. AIMS: The present study was designed to determine the relative degree to which lifetime experience with different psychedelic substances is predictive of self-reported NR among psychedelic-experienced users. METHODS: We conducted a combined reanalysis of five independent datasets (N = 3817). Using standard and regularized regression analyses, we tested the relationship between degree of experience with various psychedelic substances (binary and continuous) and NR, both within a subsample of psychedelic-experienced participants as well as the complete sample including psychedelic-naïve participants. RESULTS/OUTCOMES: Among people experienced with psychedelics, only past use of psilocybin (versus LSD, mescaline, Salvia divinorum, ketamine, and ibogaine) was a reliable predictor of NR and its subdimensions. Weaker, less reliable results were obtained for the pharmacologically similar N,N-dimethyltryptamine (DMT). Results replicate when including psychedelic-naïve participants. In addition, among people exclusively experience with psilocybin, use frequency positively predicted NR. CONCLUSIONS/INTERPRETATION: Results suggest that experience with psilocybin is the only reliable (and strongest) predictor of NR. Future research should focus on psilocybin when investigating effects of psychedelic on NR and determine whether pharmacological attributes or differences in user expectations/use settings are responsible for this observation.

N,N-Diformylmescaline: A novel analogue of mescaline detected in Queensland.

N,N-Diformylmescaline, a novel analogue of mescaline, has recently been detected in Australia in two unrelated seizures. To confirm the identification, a three-step synthesis from 3,4,5-trimethoxyphenylacetic acid was devised. However, purification of the final product proved problematic with the compound prone to degradation in solution. Analysis of the compound by LC-MS indicated that the compound was unstable under acidic and basic conditions, breaking down to N-formylmescaline. Further degradation to mescaline was observed when the compound was dissolved in hydrochloric acid for an extended period of time suggesting that N,N-diformylmescaline may be a prodrug for mescaline. The GC-MS, NMR and FTIR data for the seized compound are presented along with details of the synthesis and studies of the compound's stability in solution.

New mescaline-related N-acylhydrazone and its unsubstituted benzoyl derivative: Promising metallophores for copper-associated deleterious effects relief in Alzheimer's disease.

Alzheimer's disease (AD) is related to the presence of extracellular aggregated amyloid-ß peptide (Aß), which binds copper(II) with high affinity in its N-terminal region. In this sense, two new 1-methylimidazole-containing N-acylhydrazonic metallophores, namely, X1TMP and X1Benz, were synthesized as hydrochlorides and characterized. The compound X1TMP contains the 3,4,5-trimethoxybenzoyl moiety present in the structure of mescaline, a natural hallucinogenic protoalkaloid that occurs in some species of cacti. Single crystals of X1Benz, the unsubstituted derivative of X1TMP, were obtained. The experimental partition coefficients of both compounds were determined, as well as their apparent affinity for Cu2+ in aqueous solution. Ascorbate consumption assays showed that these N-acylhydrazones are able to lessen the production of ROS by the Cu(Aß)-system, and a short-time scale aggregation study, measured through turbidity and confirmed by TEM images, revealed their capacity in preventing Aß fibrillation at equimolar conditions in the presence and absence of copper. 1H15N HSQC NMR experiments demonstrated a direct interaction between Aß and X1Benz, the most soluble of the compounds. The Cu2+ sequestering potential of this hydrazone towards Aß was explored by 1H NMR. Although increasing amounts of X1Benz were unexpectedly not efficient at removing the metal-induced perturbations in Aß backbone amides, the broadening effects observed on the compound's signals indicate the formation of a ternary Aß­copper-X1Benz species, which can be responsible for the observed ROS-lessening and aggregation-preventing activities. Overall, the N-acylhydrazones X1TMP and X1Benz have shown promising prospects as agents for the treatment of AD.

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.

Psychedelic Drug Legislative Reform and Legalization in the US.

Importance: Psychedelic drugs are becoming accessible in the US through a patchwork of state legislative reforms. This shift necessitates consensus on treatment models, education and guidance for health care professionals, and planning for implementation and regulation. Objective: To assess trends in psychedelics legislative reform and legalization in the US to provide guidance to health care professionals, policy makers, and the public. Evidence Review: Data were compiled from legislative databases (BillTrack50, LexisNexis, and Ballotpedia) from January 1, 2019, to September 28, 2022. Legislation was identified by searching for terms related to psychedelics (eg, psilocybin, MDMA, peyote, mescaline, ibogaine, LSD, ayahuasca, and DMT). Bills were coded by an attorney along 2 axes: which psychedelic drugs would be affected and in what ways (eg, decriminalization, funding for medical research, and right to try). To explore drivers and rates of legislative reform, data were compared with other state indices including 2020 presidential voting margins and marijuana legislative reform. Findings: Twenty-five states have considered 74 bills (69 legislative initiatives, 5 ballot measures); 10 bills were enacted, and 32 were still active. The number of psychedelic reform bills introduced during each calendar year increased steadily from 5 in 2019 to 6 in 2020, 27 in 2021, and 36 in 2022. Nearly all bills specified psilocybin (67 [90%]), and many also included MDMA (3,4-methylenedioxy-methamphetamine; 27 [36%]). While bills varied in their framework, most (43 [58%]) proposed decriminalization, of which few delineated medical oversight (10 of 43 [23%]) or training and/or licensure requirements (15 of 43 [35%]). In general, bills contained less regulatory guidance than the enacted Oregon Measure 109. While early legislative efforts occurred in liberal states, the margin between liberal and conservative states has decreased over time (although the difference was not significant), suggesting that psychedelic drug reform is becoming a bipartisan issue. In addition, an analytic model based on marijuana legalization projected that a majority of states will legalize psychedelics by 2034 to 2037. Conclusions and Relevance: Legislative reform for psychedelic drugs has been proceeding in a rapid, patchwork fashion in the US. Further consideration should be given to key health care issues such as establishing (1) standards for drugs procured outside the medical establishment, (2) licensure criteria for prescribers and therapists, (3) clinical and billing infrastructure, (4) potential contraindications, and (5) use in special populations like youths, older adults, and pregnant individuals.

Mescaline: The forgotten psychedelic.

INTRODUCTION: Mescaline (3,4,5-trimethoxyphenethylamine) is one of the oldest hallucinogens, with evidence of use dating back 5700 years. Mescaline is a naturally occurring alkaloid found in cacti, mainly in the peyote cactus (Lophophora williamsii) and in the cacti of the Echinopsis genus. Since the prohibition of psychoactive substances in the early 70s, research on mescaline and other classical psychedelics has been limited. OBJECTIVES: This article aims to review the pharmacology and behavioural effects of mescaline, focusing on preclinical and clinical research. FINDINGS: Mescaline is a serotonin 5HT2A/2C receptor agonist, with its main hallucinogenic effects being mediated via its 5HT2A receptor agonist action. It also exerts effects via agonist binding at α1A/2A noradrenaline and D1/2/3 dopamine receptors. Overall, mescaline has anxiolytic-like effects in animals and increases prosocial behaviour, locomotion, and response reactivity. In humans, mescaline can induce euphoria, hallucinations, improvements in well-being and mental health conditions, and psychotomimetic effects in a naturalistic or religious setting. CONCLUSION: The pharmacological mechanisms of mescaline are similar to those of other classical psychedelics, like psilocybin and lysergic acid diethylamide (LSD). Mescaline appears to be safe to consume, with most intoxications being mild and easily treatable. Improvement in mental well-being and its ability to overcome alcoholism render mescaline potentially beneficial in clinical settings. This article is part of the Special Issue on 'Psilocybin Research'.

Associations between MDMA/ecstasy, classic psychedelics, and suicidal thoughts and behaviors in a sample of U.S. adolescents.

Suicide is one of the leading causes of death amongst adolescents and decades of research have failed to curb suicide rates within this population. There is thus a need to better understand factors that correlate with adolescent suicidal thoughts and behaviors (STBs). MDMA/ecstasy and classic psychedelics represent two areas for exploration, as use of these substances has been associated with both increased and lowered odds of STBs. Thus, the goal of this study was to test the associations between MDMA/ecstasy and classic psychedelics (psilocybin, peyote, mescaline, LSD) and STBs in a nationally representative sample of U.S. adolescents. We tested these associations in a sample of adolescents aged 12-17 years old from the National Survey on Drug Use and Health (2004-2019) (N = 262,617) using survey-weighted multivariable logistic regression models. Lifetime psilocybin use was associated with lowered odds of lifetime suicidal thinking, planning, and attempts (aOR range 0.77-0.85). Conversely, LSD was associated with increased odds of these same outcomes (aOR range 1.20-1.35). MDMA/ecstasy, peyote, and mescaline did not share associations with STBs. Our study demonstrates that individual classic psychedelics share varying relationships to STBs among adolescents. Future cross-sectional and longitudinal studies are needed to further elucidate the link between classic psychedelic use and STBs in youth.