The subiculum role on learning and memory tasks using rats and mice: A scoping review.

This scoping review aimed to systematically identify and summarize data related to subiculum involvement in learning and memory behavioral tasks in rats and mice. Following a systematic strategy based on PICO and PRISMA guidelines, we searched five indexed databases (PubMed, Web of Science, EMBASE, Scopus, and PsycInfo) using a standardized search strategy to identify peer-reviewed articles published in English (pre-registration: osf.io/hm5ea). We identified 31 articles investigating the role of the subiculum in spatial, working, and recognition memories (n = 11), memories related to addiction models (n = 9), aversive memories (n = 7), and memories related to appetitive learning (n = 5). We highlight a dissociation in the dorsoventral axis of the subiculum with many studies exploring the ventral subiculum (n = 21) but only a few exploring the dorsal one (n = 10). We also observe the necessity of more data including mice, female animals, genetic tools, and better statistical approaches for replication purposes and research refinement. These findings provide a broad framework of the subiculum involvement in learning and memory, showing essential questions that can be explored by further studies.

An open-label pilot trial assessing tolerability and feasibility of LSD microdosing in patients with major depressive disorder (LSDDEP1).

BACKGROUND: Globally, an estimated 260 million people suffer from depression [1], and there is a clear need for the development of new, alternative antidepressant therapies. In light of problems with the tolerability and efficacy of available treatments [2], a global trend is emerging for patients to self-treat depression with microdoses of psychedelic drugs such as lysergic acid diethylamide (LSD) and psilocybin [3]. Beyond anecdotal reports from those who self-medicate in this way, few clinical trials have evaluated this practice. In our recently published phase 1 study in healthy volunteers [4], we determined that LSD microdosing was relatively safe and well tolerated in that cohort. Furthermore, the data demonstrated that conducting such microdosing trials is broadly feasible, with excellent adherence and compliance to the regimen observed. In this open-label pilot trial of patients with major depressive disorder (LSDDEP1), we will test the tolerability and feasibility of an 8-week regimen of LSD microdosing in this patient group prior to a larger subsequent randomised controlled trial (LSDDEP2). METHODS: Twenty patients meeting the DSM-5 criteria for major depressive disorder will receive an 8-week LSD microdosing treatment regimen. The treatment protocol will use a sublingual formulation of LSD (MB-22001) delivered twice per week under a titration schedule using a dose of 5-15 µg. Tolerability will be assessed by quantifying the percentage of participants who withdraw from the trial due to adverse events attributable to the treatment regimen, while feasibility will be assessed by quantifying the percentage of attended clinic visits once enrolled. To determine whether there is any antidepressant response to the LSD microdosing regimen, MADRS scores will be assessed at baseline and 2, 4, 6, and 8 weeks after the commencement of the regimen. DISCUSSION: The results of LSDDEP1 will provide valuable information regarding the tolerability and feasibility of a proposed LSD microdosing regimen in patients with MDD. Such information is critically important to optimise trial design prior to commencing a subsequent and more resource-intensive randomised controlled trial. TRIAL REGISTRATION: ANZCTR, ACTRN12623000486628. Registered on 12 May 2023.

The current state of ayahuasca research in animal models: A systematic review.

RATIONALE: The psychedelic brew ayahuasca is increasingly being investigated for its therapeutic potential. Animal models are essential to investigate the pharmacological effects of ayahuasca since they can control important factors influencing it, such as the set and setting. OBJECTIVE: Review and summarise data available on ayahuasca research using animal models. METHODS: We systematically searched five databases (PubMed, Web of Science, EMBASE, LILACS and PsycInfo) for peer-reviewed studies in English, Portuguese or Spanish published up to July 2022. The search strategy included ayahuasca- and animal model-related terms adapted from the SYRCLE search syntax. RESULTS: We identified 32 studies investigating ayahuasca effects on toxicological, behavioural and (neuro)biological parameters in rodents, primates and zebrafish. Toxicological results show that ayahuasca is safe at ceremonial-based doses but toxic at high doses. Behavioural results indicate an antidepressant effect and a potential to reduce the reward effects of ethanol and amphetamines, while the anxiety-related outcomes are yet inconclusive; also, ayahuasca can influence locomotor activity, highlighting the importance of controlling the analysis for locomotion when using tasks depending on it. Neurobiological results show that ayahuasca affects brain structures involved in memory, emotion and learning and that other neuropathways, besides the serotonergic action, are important in modulating its effects. CONCLUSIONS: Studies using animal models indicate that ayahuasca is toxicologically safe in ceremonial-comparable doses and indicates a therapeutic potential for depression and substance use disorder while not supporting an anxiolytic effect. Essential gaps in the ayahuasca field can still be sufficed using animal models.

LSD and language: Decreased structural connectivity, increased semantic similarity, changed vocabulary in healthy individuals.

Language has been explored as a window into the mind. Psychedelics, known to affect perception and cognition, seem to change language, but a systematic, time-dependent exploration is lacking. Therefore, we aimed at mapping the psychedelic effects on language over the time course of the acute and sub-acute effects in an explorative manner. For this, 24 healthy volunteers (age [mean±SD, range]: 35±11, 25-61 years; 33% women) received 50 µg lysergic acid diethylamide (LSD) or inactive placebo in a randomized, double-blind, placebo-controlled, crossover study. We assessed different language productions (experience reporting, storytelling), components (structure, semantics, vocabulary) and time points (+0 h to +24 h). Language productions included 5-min experience reporting (+1.5 h, +6.5 h) and 1-min storytelling (+0 h, +2 h, +4 h, +6 h, +24 h). Language structure was assessed by computing speech topology (SpeechGraphs), semantics by semantic distances (FastText), vocabulary by word categories (LIWC). LSD, compared to placebo, changed language structure, including decreased verbosity, lexicon, global and local connectivity (+1.5 h to +4 h); decreased semantic distances between neighbouring words and overall words (+2 h to +24 h); and changed vocabulary related to grammar, persons, time, space and biological processes (+1.5 h to +24 h). In conclusion, low to moderate LSD doses changed language over diverse production types, components and time points. While simpler and disconnected structure and semantic similarity might reflect cognitive impairments, changed vocabulary might reflect subjective perceptions. Therefore, language under LSD might provide a window into the psychedelic mind and automated language quantifications should be better explored as valuable tools to yield more unconstrained insights into psychedelic perception and cognition.

Cannabis use, risk behaviours and harms in Brazil: A comprehensive review of available data indicators.

ISSUES: Cannabis use and related health/social outcome indicator data for Brazil-where non-medical cannabis is generally illegal-are limited. APPROACH: Towards a comprehensive overview of relevant indicators, we searched primary databases by combining MeSH-index terms related to cannabis, geographic location and subtopic terms (e.g., use, health, mortality) focusing on cannabis use and key outcome indicators in Brazil since 2010. In addition, relevant 'grey literature' (e.g., survey reports) was identified. Key indicator data were mainly narratively summarised. KEY FINDINGS: Overall, cannabis use has increased somewhat since pre-2010, with (past-year) use rates measured at 2-3% for general population adults, yet 5% or higher among youth and/or (e.g., post-secondary) student populations. For key risk behaviours, the presence of tetrahydrocannabinol-positivity among motor-vehicle drivers has been measured at <2%. While the prevalence of cannabis use disorder appears to have decreased, the relative proportion of treatment provided for cannabis-related problems increased. National- and local-based studies indicated an association of cannabis use with mental health harms, including depression and suicidality. Although some non-representative and/or local studies contain information, other monitoring data, including cannabis-related risks and harms (e.g., cannabis-related driving, mortality, hospitalisations), are limited in availability. IMPLICATIONS AND CONCLUSION: The prevalence of cannabis use in Brazil is comparably low (e.g., relative to elsewhere in the Americas). Data on numerous key cannabis-related indicators is absent, or limited in scope for Brazil. Considering ongoing evolutions in cannabis control and its status as the most common illicit drug, more comprehensive surveillance of cannabis use and related outcomes is advised.

Ayahuasca's therapeutic potential: What we know - and what not.

The therapeutic potential of the psychedelic brew ayahuasca has been investigated in preclinical and clinical studies. Currently, the most consistent evidence refers to depression. However, various studies suggest that ayahuasca may comprise therapeutic benefits in other health conditions. This narrative review provides a comprehensive, up-to-date overview of ayahuasca's therapeutic effects in diverse clinical conditions in human (clinical, cross-sectional, observational, and qualitative) and preclinical (animal and in vitro) studies. In addition to summarizing and discussing the most commonly studied conditions, such as depression, anxiety, and substance use disorders (SUD), we also examine less frequently studied psychiatric, neurological, and physical conditions. Moreover, we discuss evidence from epidemiological studies on the impact of regular, long-term ayahuasca use on health and psychosocial outcomes. Overall, evidence for depression and SUD is more consistent, with numerous and diverse studies. However, a growing body of evidence suggests that other conditions equally relevant to public health might be promising targets for ayahuasca's therapeutic effects. This includes preliminary studies indicating potential for grief, eating disorders, posttraumatic stress disorder, personality disorders, Parkinson's and Alzheimer's disease, and severe physical illnesses (e.g., cancer, chronic conditions). Moreover, preliminary evidence in long-term ayahuasca users does not suggest detrimental effects but possible benefits for individual and collective health. In light of the emerging evidence of psychedelic drugs as therapeutic agents, it is essential to further investigate in rigorous designs the therapeutic potential of ayahuasca in conditions other than depression.

Beyond ANOVA and MANOVA for repeated measures: Advantages of generalized estimated equations and generalized linear mixed models and its use in neuroscience research.

In neuroscience research, longitudinal data are often analysed using analysis of variance (ANOVA) and multivariate analysis of variance (MANOVA) for repeated measures (rmANOVA/rmMANOVA). However, these analyses have special requirements: The variances of the differences between all possible pairs of within-subject conditions (i.e., levels of the independent variable) must be equal. They are also limited to fixed repeated time intervals and are sensitive to missing data. In contrast, other models, such as the generalized estimating equations (GEE) and the generalized linear mixed models (GLMM), suggest another way to think about the data and the studied phenomenon. Instead of forcing the data into the ANOVAs assumptions, it is possible to design a flexible/personalized model according to the nature of the dependent variable. We discuss some advantages of GEE and GLMM as alternatives to rmANOVA and rmMANOVA in neuroscience research, including the possibility of using different distributions for the parameters of the dependent variable, a better approach for different time length points, and better adjustment to missing data. We illustrate these advantages by showing a comparison between rmANOVA and GEE in a real example and providing the data and a tutorial code to reproduce these analyses in R. We conclude that GEE and GLMM may provide more reliable results when compared to rmANOVA and rmMANOVA in neuroscience research, especially in small sample sizes with unbalanced longitudinal designs with or without missing data.

Identifying risk-thresholds for the association between frequency of cannabis use and development of cannabis use disorder: A systematic review and meta-analysis.

BACKGROUND: Cannabis use disorder (CUD) affects one-in-five cannabis users, presenting a major contributor to cannabis-associated disease burden. Epidemiological data identify the frequency of cannabis use as a risk factor for CUD. This review aimed to determine quantifiable risk-thresholds of the frequency of cannabis use for developing CUD. METHODS: Systematic search of Medline, EMBASE, PsycInfo, CINAHL, and Web of Science for cohort/case-control studies that assessed the association between frequency of cannabis use and CUD from 2000 to 2022. Effect estimates were converted to risk ratios (RR). A random-effects multi-level multivariate meta-analytic approach was utilized, and sensitivity analyses conducted. Quality of included studies was assessed with the Newcastle Ottawa Scale. RESULTS: Six prospective cohort studies were included in this review, drawn from two main source studies. Random-effect modeling showed a significant log-linear dose-response association between the frequency of cannabis use and CUD risk (p < 0.0001). The risk of CUD increased from RR:2.03 (95% CI:1.85-2.22) for 'yearly' use, to RR:4.12 (95% CI:3.44-4.95) for 'monthly" use, RR:8.37 (95% CI:6.37-11.00) for 'weekly' use, and RR:16.99 (95% CI:11.80-24.46) for 'daily' use. Multi-level modeling showed an absolute risk increase (ARI) from 3.5% (95% CI:2.6-4.7) for 'yearly' use, to 8.0% (95% CI:5.3-12.1) for 'monthly' use, to 16.8% (95% CI:8.8-32.0) for 'weekly' use, and 36% (95% CI:27.047.9) for 'daily' use. CONCLUSION: A limited risk of CUD as a potential outcome of cannabis use exists even at infrequent levels of use, but significantly increases as frequency of use increases. Corresponding information should be conveyed to cannabis users as part of targeted prevention messaging to promote safer cannabis use.

Conceptualizing and considering Cannabis-Related "Harm-to-Others": The Role of Cannabis-Related Violence.

Public health-oriented frameworks for cannabis use of control, including legalization, are evolving. Most frameworks aim to reduce cannabis-related health harms that materialize among users; there has been comparably limited focus on cannabis-related "harm-to-others". A longstanding issue for other psychoactive substances, and increasingly recognized form of cannabis-related harm-to-others involves violence/aggression. We briefly review relevant epidemiological and psycho-behavioral data related to cannabis-related violence and aggression, and discuss intervention prospects. Systematic review and other study data show a moderately positive association between cannabis use and perpetration of physical (including intimate-partner) violence, for example involving assault, aggression, and fighting; this risk may be further elevated by intensive use patterns. Such harms may involve injuries/deaths and contribute to the cannabis-related burden of disease. Within the contexts of public health-oriented frameworks for cannabis control, greater awareness and targeted interventions regarding the risk for exposure to violence related to cannabis use should be promoted in addition to protections for users' health.

Psychosocial and Drug Use Assessment of Regular vs. Non-Regular Ayahuasca Users in a Brazilian Sample: a Web-Based Survey.

Background: Preliminary evidence suggests that long-term ayahuasca use is associated with better psychosocial outcomes and less drug use; however, available data on the association between ayahuasca intake frequency and psychosocial outcomes is limited. Objectives: We sought to characterize and investigate the association of regular ayahuasca use, as compared to non-regular use, on licit (alcohol and tobacco) and illicit (cannabis, psychostimulants, psychedelics, and non-medical opioids) drug use and psychosocial outcomes. Methods: An online-based cross-sectional survey was taken among people who use ayahuasca in Brazil assessing sociodemographic, drug and ayahuasca use, anxiety and depression (HAD-S), intrinsic religiosity (IRI), negative and positive affects (PANAS), satisfaction with life (SWLS), and five quality of life domains (WHOQOL-Brief). Multivariate regressions for each psychosocial outcome and drug use were performed comparing regular to non-regular ayahuasca users while correcting for sociodemographic variables. Results: A total of 286 valid answers were retrieved, divided into people with regular (n = 101) and non-regular (n = 185) ayahuasca use. Groups had similar sociodemographic profiles and lifetime use of drugs. In the multivariate analysis, regular use of ayahuasca was associated with lower anxiety (B: -0.97), negative affect (B: -2.62), general (B: 0.22) and physical (B: 0.17) quality of life, higher intrinsic religiosity scores (B: 4.16), and less past-month licit (OR = 0.30) and illicit (OR = 0.49) use of substances. Conclusions: Our results show that ceremonial regular ayahuasca compared to non-regular use is associated with better psychosocial and mental health outcomes and less drug use. Studies with repeated ayahuasca administration and extended follow-ups are essential to clarify the nature of ayahuasca's therapeutic effects and to guide future clinical research.

Effects of repeated ayahuasca administration on behaviour and c-Fos expression in male rats exposed to the open field.

Considering the long-lasting effects of ayahuasca on the brain and emotional processing, the objective of this study was to evaluate the behavioural and neurobiological effects of repeated ayahuasca administration in an animal model of exploratory behaviour related to novel-environment anxiety. Male Wistar rats received water, 120, 240, 480 or 3600 mg/kg of resuspended freeze-dried ayahuasca by gavage once a day for 30 days; there was also a non-manipulated homecage group. One hour after the last administration, animals were placed individually in the open field for 20 min. We analysed the weight gain, the behavioural response through a stochastic analysis, and c-Fos immunoreactive levels in the hippocampus, amygdala, pre-frontal and barrel field cortex. Ayahuasca at 120 mg/kg increased ambulation, and at 3600 mg/kg decreased vertical exploration and reduced weight gain. Aya3600 had higher c-Fos expression in regions of the hippocampus and infralimbic cortex than homecage, water or aya120 groups. Water-receiving animals had less c-Fos expression in the anterior basolateral amygdala than others groups. Our results show different behavioural effects of ayahuasca: a stimulant-like effect in small doses, and decreased activity in extreme high-dose, probably due to adverse effects. Higher activation of areas involved in emotional processing and the serotonergic pathway adds to the neurobiological literature on repeated/chronic ingestion of ayahuasca. Our data do not support an anxiolytic effect of repeated ayahuasca related to exploring new anxiogenic-environment but suggest that low ayahuasca doses should be further studied. The absence of severe impairment and behavioural syntax alteration reinforce ayahuasca safety.

LSD and creativity: Increased novelty and symbolic thinking, decreased utility and convergent thinking.

BACKGROUND: Controversy surrounds psychedelics and their potential to boost creativity. To date, psychedelic studies lack a uniform conceptualization of creativity and methodologically rigorous designs. AIMS: This study aimed at addressing previous issues by examining the effects of lysergic acid diethylamide (LSD) on creativity using multimodal tasks and multidimensional approaches. METHODS: In a randomized, double-blind, placebo-controlled, crossover study, 24 healthy volunteers received 50 µg of LSD or inactive placebo. Near drug peak, a creativity task battery was applied, including pattern meaning task (PMT), alternate uses task (AUT), picture concept task (PCT), creative metaphors task (MET) and figural creativity task (FIG). Creativity was assessed by scoring creativity criteria (novelty, utility, surprise), calculating divergent thinking (fluency, originality, flexibility, elaboration) and convergent thinking, computing semantic distances (semantic spread, semantic steps) and searching for data-driven special features. RESULTS: LSD, compared to placebo, changed several creativity measurements pointing to three overall LSD-induced phenomena: (1) 'pattern break', reflected by increased novelty, surprise, originality and semantic distances; (2) decreased 'organization', reflected by decreased utility, convergent thinking and, marginally, elaboration; and (3) 'meaning', reflected by increased symbolic thinking and ambiguity in the data-driven results. CONCLUSION: LSD changed creativity across modalities and measurement approaches. Three phenomena of pattern break, disorganization and meaning seemed to fundamentally influence creative cognition and behaviour pointing to a shift of cognitive resources 'away from normal' and 'towards the new'. LSD-induced symbolic thinking might provide a tool to support treatment efficiency in psychedelic-assisted therapy.

Ayahuasca and tobacco smoking cessation: results from an online survey in Brazil.

RATIONALE: Smoking-related disease is a major problem globally. Effective smoking cessation treatments are however limited. Increasing evidence suggests that psychedelics have potential as treatments for substance use disorders and may therefore prove an option in aiding smoking cessation. OBJECTIVES: To establish which factors predict smoking cessation in people who reported quitting or reducing smoking following ayahuasca consumption. METHODS: A retrospective cross-sectional mixed-method study (quantitative and qualitative design) was undertaken using data from an online survey evaluating peoples' experiences before and after drinking ayahuasca. Multivariate logistic regression was performed with smoking condition (cessation or reduction/relapse) as a dependent variable and demographics, smoking, ayahuasca-related variables and the mystical experience (MEQ30) as predicting factors. RESULTS: A total of 441 responses were grouped according to self-reported smoking status: cessation (n = 305) or reduction/relapse (n = 136) smoking. Logistic regression showed that mystical experience (OR: 1.03; 95% CI [1.00-1.05]) and frequency of ayahuasca intake (OR: 2.16[1.00-4.70]) were protective factors, while positive mood (measured by the MEQ30) during the ayahuasca experience was a risk factor (OR: 0.91[0.85-0.97]). Qualitative thematic analysis identified eight themes (e.g. acquired awareness, spiritual experience, increased motivation) related to the ayahuasca experience and the process of smoking cessation/reduction. CONCLUSIONS: Our results suggest that ayahuasca could be used as a potential tool for smoking cessation, and that effects may be mediated by mystical experience. Given the current burden of smoking-related disease and the limited treatment options, studies are needed to investigate the efficacy of psychedelics in smoking cessation.

Ayahuasca Lyophilization (Freeze-drying) Protocol with Pre- and Post-procedure Alkaloids Quantification.

Ayahuasca is a psychoactive brew from the decoction of different Amazonian plants, traditionally used in several cultures, religions, and rituals. Scientific studies with ayahuasca are rapidly increasing due to its subjective effects and therapeutic potential. Although ayahuasca is traditionally used in its liquid presentation, lyophilized (freeze-dried) ayahuasca is often used in scientific experimentation settings. However, there is no standard process or guideline to freeze-dry ayahuasca nor comparison of the chemical profile between the liquid and freeze-dried presentations. Therefore, we describe a reproducible five-day protocol for ayahuasca lyophilization with alkaloids quantification by liquid chromatography coupled to tandem mass spectrometry of both the liquid and the final freeze-dried ayahuasca. By the end of the protocol, approximately 295 g of freeze-dried extract with similar alkaloids concentration were obtained from two liters of ayahuasca (dry matter: 14.75 %). The final extract was stored for three years inside a vacuum desiccator (approximately 6°C) with its texture quality preserved. Further studies should address the impact of different storage conditions and the lyophilization on the alkaloids' quantity of the freeze-dried ayahuasca, especially the use of heat in regards to the ß-carbolines.

Co-exposure of cannabinoids with amphetamines and biological, behavioural and health outcomes: a scoping review of animal and human studies.

RATIONALE: The growing prevalence of psychostimulant (including amphetamine) use and associated health harms, with limited treatment options, present a global challenge. There is an increasing availability and medical applications of cannabinoids, and growing interest in their therapeutic potential for addictive disorders. OBJECTIVES: The objective of this study is to review available data regarding cannabis/cannabinoid co-use or exposure on amphetamine-related outcomes. METHODS: Towards the present scoping review, we systematically searched four databases (Medline, Web-of-Science, CINAHL Plus and PsycInfo) using cannabis/cannabinoid and amphetamine text-terms identifying peer-reviewed, English-language studies published in 2000-2020 involving multiple methods approaches among both human and animal study samples, assessing the association of co-use/administration of cannabis/cannabinoids products with non-medical amphetamines on biological, behavioural or health outcomes. RESULTS: Twenty-five articles were included. Pre-clinical studies (n = 15) found mostly protective effects of single or repeated cannabinoids administration on rodents in amphetamine addiction models, amphetamine-induced models of human mental disorders (e.g. schizophrenia) and amphetamine-induced neurotoxicity. Human studies (n = 10) were more heterogeneously designed (e.g. cross-sectional, case-control, longitudinal) and assessed natural ongoing cannabis and methamphetamine use or dependence, showing mostly enhanced harms in a diversity of outcomes (e.g. mental health, methamphetamine use, cognition). CONCLUSIONS: While human studies suggest cannabis use as an adverse risk factor among non-medical amphetamine users, pre-clinical studies suggest therapeutic potential of cannabinoids, especially cannabidiol, to alleviate amphetamine addiction and harms, including treatment outcomes. Given increasing psychostimulant harms but lack of care options, rigorous, high-quality design studies should aim to translate and investigate pre-clinical study results for potential therapeutic benefits of cannabinoids for amphetamine use/abuse in human subjects.

Co-exposure of cocaine and cannabinoids and its association with select biological, behavioural and health outcomes: A systematic scoping review of multi-disciplinary studies.

Cocaine use entails severe health- and social-related harms globally. Treatment options for cocaine dependence are highly limited. Benefits of cannabinoids for addiction have been documented, making it opportune to examine existing data on the possible outcomes associated with cannabinoids and cocaine co-use. We conducted a systematic scoping review following the PRISMA guidelines of peer-reviewed, English-language studies published from 2000 to 2021 in four databases (Medline, Web-of-Science, CINAHL Plus, and PsycInfo), assessing the co-exposure of cannabis/cannabinoids with cocaine on behavioural, biological or health outcomes. Both quantitative and qualitative, as well as humans and pre-clinical animals' studies (n=46) were included. Pre-clinical studies (n=19) showed mostly protective effects of cannabidiol (CBD) administration on animal models of addiction (e.g., cocaine-craving, -relapse, and -withdrawal) and cocaine-toxicity. Tetrahydrocannabinol (THC) had more inconsistent results, with both protective and counter-protective effects. Human studies (n=27) were more heterogeneous and assessed natural ongoing cannabis and cocaine use or dependence. Quantitative-based studies showed mostly enhanced harms in several outcomes (e.g., cocaine use, mental health); two available clinical trials found no effect upon CBD administration on cocaine-related treatment outcomes. Qualitative data-based studies reported cannabis use as a substitute for or to alleviate harms of crack-cocaine use. While pre-clinical studies suggest a potential of cannabinoids, especially CBD, to treat cocaine addiction, the few trials conducted in humans found no benefits. Cannabis co-use by cocaine users commonly presents a risk factor, entailing enhanced harms for users. More rigorous, controlled trials are still necessary to investigate cannabinoids' potential considering pre-clinical findings and reported benefits from specific drug users.

Why comparative epidemiological indicators suggest that New Zealand is unlikely to experience a severe opioid epidemic.

North America (i.e., the United States and Canada) and select other wealthy Commonwealth countries (e.g., Australia, the UK) have been experiencing marked 'opioid epidemics', consisting of elevated opioid use and related (e.g., mortality and morbidity) harms involving both prescription and, increasingly, illicit opioid substances. Multiple commentators have alerted to the possibility of New Zealand becoming home to a similar opioid crisis. In this article, we briefly examine and compare key system-level epidemiological indicators for New Zealand in regards to this situation and prospect. These data suggest that, comparatively, population-level (medical) opioid use, exposure and supply in New Zealand have been low and moderate, mostly involving restrained and lower-risk (e.g., short-duration, few long-acting/high-potency formulations, restricted settings) medical opioid availability, with limited over-time increases and absent the major oscillations in opioid dispensing observed elsewhere. Similarly, illicit opioids have been rather low in availability and use, and do not form primary substances in illicit drug scenes or markets. Correspondingly, opioid-related mortality in New Zealand has been somewhat increasing over-time albeit at comparably low levels, and principally involves methadone, morphine and codeine, i.e. the main opioids medically prescribed. Synthesizing the evidence, New Zealand has not featured the distinct characteristics or system-level drivers that have facilitated the opioid epidemics as have unfolded in other jurisdictions. It appears that New Zealand may have all along engaged in the more measured opioid use practices that other jurisdictions have attempted to revert to post-hoc (but largely when too late) while experiencing extensive adverse consequences related to opioids. On this basis, New Zealand provides for a worthwhile comparative case study towards more moderate opioid utilization and control entailing relatively limited collateral harms (e.g., opioid mortality) on public health compared to elsewhere. Details and characteristics of New Zealand's approach to and experience with opioids should be further examined for future and other jurisdictions' benefit.

'Resurgent', 'twin' or 'silent' epidemic? A select data overview and observations on increasing psycho-stimulant use and harms in North America.

In the early 2000s, increasing prevalence of psycho-stimulant (e.g., crack/cocaine, methamphetamine) use and related harms, including severe adverse health outcomes, was observed among - mostly marginalized - populations of persons using illicit drugs in North America, underscoring an urgent need for interventions options towards improved prevention and treatment. By about 2010, however, the 'opioid crisis', featuring unprecedented use and public health burden, had accelerated into full force in North America, largely muting attention to the psycho-stimulant issue until recently. Recent surveillance data on drug use and related mortality/morbidity from the present decade has documented a marked resurgence of psycho-stimulant use and harms especially in at-risk populations, commonly in direct combination with opioids, across North America, resulting in a 'twin epidemic' comprised of opioids and psycho-stimulants We briefly review select epidemiological data indicators for these developments from the United States and Canada; in the latter jurisdiction, related evidence has been less prevalent and systematic but corroborating the same trends. Evidently, the (widely ongoing) focus on the 'opioid epidemic' as a 'mono-type' drug problem has become an anachronism that requires urgent and appropriate correction. We then briefly consider existing, evidence-based options for - prevention and treatment - interventions targeting psycho-stimulant use and harms, which are substantially more limited and/or less efficacious than those available for problematic opioid use, while presenting major gaps and challenges. The observed resurgence of psycho-stimulants may, indirectly, relate to recent efforts towards curtailing (medical) opioid availability, thereby accelerating demand and supply for both illicit opioids and psycho-stimulants. The presently unfolding 'twin epidemic' of opioids and psycho-stimulants, combined with limited intervention resources, presents an acute challenge for public health and may crucially undermine actively extensive efforts to reduce opioid-related health harms in North America.

Opioid use, regulation, and harms in Brazil: a comprehensive narrative overview of available data and indicators.

BACKGROUND: Global opioid consumption increased multifold post-2000, disproportionately in high-income countries, with severe mortality/morbidity consequences. Latin America features comparatively low opioid availability; Brazil, the region's most populous country, makes an interesting case study concerning opioid use/harms. In this comprehensive overview, we aimed to identify and summarize medical and non-medical data and indicators of opioid availability and use, regulation/control, and harm outcomes in Brazil since 2000. METHODS: We searched multiple scientific databases to identify relevant publications and conducted additional 'grey' literature searches to identify other pertinent information. RESULTS: Despite some essential indicators, opioid-related data are limited for Brazil. Data indicate that population-level availability of prescription opioids represents only a small fraction of use in comparison to high-income countries. However, within Latin America, Brazil ranks mid-level for opioid consumption, indicating relatively moderate consumption compared to neighboring jurisdictions. Brazil has implemented restrictive regulations to opioid prescribing and is considered 'highly restricted' for opioid access. Codeine remains the major opioid analgesic utilized, but stronger opioids such as oxycodone are becoming more common. Professional knowledge regarding medical opioid use and effects appears limited. National surveys indicate increases in non-medical use of prescription opioids, albeit lower than observed in North America, while illicit opioids (e.g., heroin) are highly uncommon. CONCLUSIONS: Overall population-level opioid availability and corresponding levels of opioid-related harms in Brazil remain substantially lower than rates reported for North America. However, the available surveillance and analytical data on opioid use, policy/practice, and harms in Brazil are limited and insufficient. Since existing and acute (e.g., pain-related) needs for improved opioid utilization and practice appear to be substantiated, improved indicators for and understanding of opioid use, practice, and harms in Brazil are required.

Comparison of Crude Population-Level Indicators of Opioid Use and Related Harm in New Zealand and Ontario (Canada).

North America and select other Commonwealth jurisdictions have been experiencing unprecedented opioid epidemics characterized by excessive and persistently high levels of opioid misuse, morbidity and mortality, and related disease burden. Recent discussions have considered whether New Zealand might undergo or needs to expect a similar 'opioid crisis'. Towards further informing these considerations, we examine and compare essential, publicly available indicators of opioid utilization and harms (mortality) from New Zealand and the Canadian province of Ontario, due to the fact that both operate public health care systems in similar socio-cultural settings. We find that the two jurisdictions have featured vastly different population levels of opioid exposure, opioid consumption patterns (e.g., high-dose/long-term/high-risk prescribing) known as key predictors of adverse outcomes, and levels of opioid mortality as evidenced by concrete epidemiological indicators and data. Specifically for opioid-related death rates, these were already approximately threefold higher in Ontario compared to New Zealand based on most recent comparison data (e.g., 2012); these differentials have likely further grown more recently given major and distinct changes in population-level opioid exposure and risks, and subsequent opioid-related deaths since then in Ontario. Based on the present data and related evidence, New Zealand does not seem to need to anticipate an opioid mortality epidemic similar to that experienced in North America; however, it would be of interest to establish more comprehensive and timely surveillance of key system-level indicators of opioid use and harms as are standard in North America. As such, this inter-jurisdictional comparison makes for a case study in starkly contrasting scenarios of opioid use and harms, the drivers behind which deserve further systematic examination.