All participants receive an honorarium of $C40 at each biannual visit for their time, expertise and travel. To capture initial episodes of suicidality, analyses for this study were restricted to AESHA participants who had never thought about or attempted suicide at base line and completed at least one follow-up visit between January 2010 and August 2014. Those with missing observations for suicidality at baseline were excluded from analysis, and one additional participant was excluded because reported suicidality was missing at follow-up.This study demonstrated that among marginalised women, many of whom are street-involved and experience a disproportionate burden of violence, trauma, psycho logical distress and suicide, naturalistic psychedelic drug use predicted a significantly reduced hazard for suicidality. Crystal methamphetamine use and childhood abuse predisposed women to suicidality corresponding to more than a threefold increased hazard. Suicidality was highly prevalent, with almost half of women reporting lifetime suicidality at baseline, and 11% reporting a first episode of suicidality in the last 6months during follow-up. Few studies have longitudinally examined predictors of suicidality among marginalised sex workers, and of the avail able data, most are cross-sectional and/or conducted in lower-income and middle-income settings.The present study, based on a community-based, prospective cohort of marginalised women, adds to a growing body of literature documenting the protective and therapeutic potentials of psychedelic substances.Data were self-reported, and questions pertaining to events that occurred in the past may be subject to recallbias. Variables examined included sensitive and highly stigmatised topics such as childhood trauma, violence and illicit drug use,greenhouse vertical farming which introduce the potential for social desirability and reporting bias.

However, the likelihood of these biases is reduced by the community-based nature of the study. While lifetime psychedelic drug use was found to reduce the hazard of suicidality, the associations uncovered in this analysis cannot be determined as causal. However, the use of Cox regression analysis in this study was able to determine a temporal relationship between psychedelic use and suicidality. The sample was restricted to participants who had not experienced suicidal ideation or attempt at baseline, ensuring that psychedelic use preceded suicidality and thus providing evidence that psychedelics have a protective effect. Due to a lack of statistical power, analyses evaluating the effects of more nuanced indicators of psychedelic use , as well as separate analyses for ideation and attempt outcomes, were not feasible. Further exam ination of these variables would certainly be interesting and important in future analyses with additional data from follow-up questionnaires. Suicidality is influenced by complex individual, interpersonal and structural variables, and not all potential confounding variables could be controlled for in this study. For example, women who use psychedelics may also possess some characteristic associated with a reduced likelihood of being suicidal , which were not examined in this study. Despite the relative safety of psychedelic drug use as evidenced from the clinical and non-clinical literature,it should be noted that the use of psychedelics, particularly with unknown doses sourced from unregulated street markets, is not without risk, highlighting the importance of set and setting; the doses and contexts of psychedelic use among women in the present study could not be determined. The SE for the association between psychedelic use and suicidality was somewhat high, resulting in a wider CI. However, a large and significant protective effect was demonstrated in multivariable analysis, despite the relatively small number of events for suicidality over follow-up. With a larger sample size, we would expect a narrower CI for this association. The study population included women from a wide-ranging representation of sex work environments, yet findings may not be fully generalisable to sex workers in other settings.

The mapping of working areas and time–location sampling helped to ensure a representative sample and to minimise selection bias. To the best of our knowledge, this study is the first to longitudinally investigate associations with suicidality among marginalised and street-involved sex workers in North America and builds on prior cross-sectional research highlighting significantly elevated rates of suicidality and unmet mental health needs in this population. For example, a study conducted in Sydney, Australia demon strated significant links between depression, trauma, and suicidality, where an estimated 42% of street-based female sex workers reported attempting suicide and 74% reported lifetime suicidal ideation.While estimates of mental illness vary significantly across sex work settings, up to three-quarters of street-involved and drug-involved sex workers in a US study reported severe depression, anxiety or PTSD.Notably, our study demonstrated a lower risk of suicidality among women working indoors in bivariate analysis , lending support to the critical role of safer workplace environments in mitigating risk. In studies conducted in Asia, recent suicide attempts ranged from 19% among sex workers in Goa, India to 38% among sex workers in China,many of whom work in marginalised settings with few workplace protections. Transgender women involved in sex work, a sub-population experiencing significant psychosocial vulnerability and discrimination, report notably further elevated rates of suicidality: three-quarters of participants in San Francisco reported suicide ideation, of whom 64% attempted suicide.The global evidence is unequivocal that in settings where sex work is criminalised, sex workers are unable to access essential social, health and legal protections , highlighting the need for structural and community-led interventions to improve health and human rights.A structural approach to mitigating suicidality risk requires a reform of laws and policies that perpetuate stigma, discrimination, violence and unequal access to health and social supports among sex workers. Increased support for community-driven interventions that are gender and culturally appropriate are urgently needed, and any clinical treatment utilising psychedelics must be developed alongside sex worker-led interventions and community empowerment.

Our findings extend on research on associations between lifetime use of illicit drugs and increased risk for suicidality: in bivariate analysis, all classes of illicit drugs were demonstrated to increase the hazard of suicidality with the exception of psychedelics. In multivariable analysis, psychedelics were independently associated with a 60% reduced hazard for suicidality, contributing to emergent evidence on the potential of psychedelics to mitigate risks for suicide. Among the various scientific studies examining the potential benefits of psychedelic drug use, a recent and large population study conducted among adult respondents in the USA demonstrated that psyche delics are associated with reduced psychological distress and suicidality.A recent open-label trial conducted in the UK demonstrated the safety and efficacy of psilocybin for treating major depression, and another open-label trial in Brazil found rapid and sustained antidepressant effects from the Amazonian psychedelic brew ayahuasca administered in a clinical setting.The ways in which psychedelics may alleviate suffering associated with some mental illness is undoubtedly a complex phenomenon. It has been hypothesised that psychedelics modify neurobiological processes that may be involved in suicidality by down regulating 5-HT2A serotonin receptors,vertical farming investment as increased binding of this receptor has been implicated in major depression and suicide.Further more, there is evidence that psychedelics alter neural network connectivity and enhance recall of autobiograph ical memories, which may facilitate positive reprocessing of trauma.Recent randomised, placebo-controlled, crossover studies found that psilocybin and LSD were associated with increased positive mood and psychological well-being,supporting other work demonstrating the anti-depressive/ anxiolytic effects of psychedelics.The potential of psychedelics to elicit ‘mystical-type’ experiences, with profound and sustained positive changes in attitudes and mood, may play a key role in addiction treatment interventions.For example, psilocybin-assisted psychotherapy demonstrated high success in smoking cessation outcomes at 6months follow-up , and mystical experiences generated from the psilocybin sessions were significantly correlated with elevated ratings of personal meaningfulness, well-being and life satisfaction.Randomised control trials in the USA and Switzerland have demonstrated significant long term improvements among patients with treatment-resis tant PTSD following MDMA-assisted psychotherapy, and further research is continuing in an international multisite phase t3 clinical trial. Marginalised and street-based sex workers experience complex and synergistic effects between trauma, lack of workplace safety and mental health/substance use comorbidities that elevate risk of suicidality.

Marginal ised women and sex workers who use drugs report high rates of childhood abuse,which is associated with an increased likelihood of experiencing subsequent physical or sexual violence, as well as initiating injection drug use.For those suffering from emotional trauma stemming from violence, including indirect violence , there may be a proclivity to use drugs for self-medication. Violence and sexual coercion have been found to be significantly associated with suicidality among sex worker populations in China and India.As demonstrated in this study, having an early traumatic life event is a key risk factor for suicide among sex workers, a high proportion of whom are Indigenous, and experiencing historical trauma can have harmful intergenerational impacts.Given that historical experiences of violence and trauma denote significant risk for suicide, there is an urgent need to provide integrated, trauma-informed intervention services for sex workers and other marginalised populations. Currently available interventions and pharmaco logical treatments for suicidality show limited efficacy, and concerted efforts should be made to increase access to evidence-based treatments and to explore alternative approaches to improving mental health and well-being. Emerging research and evidence show positive outcomes with psychedelic-assisted treatments, which have demonstrated an excellent record of safety with few to no serious adverse effects reported.This study suggests psychedelic substances may hold promise as useful tools in addressing mental health issues and remediating risks for psychological distress and suicide.The increasing spread of marijuana use, especially among adolescents and young adults , has heightened societal awareness of the risks associated with this drug and has highlighted the need to fully understand its mechanism of action. Basic research has shown that D9 -tetrahydrocannabinol , the main active constituent of marijuana, produces its effects by combining with selective receptors present on the membrane of cells in the brain, the vasculature and the immune system . Research has also revealed that a group of lipid-derived substances produced by the body engages these receptors and participates in bio logical processes as diverse as painperception, memory formation and blood pressure regulation. This knowledge has allowed researchers to interpret the pharmacological properties of marijuana, but remains inadequate to the task of developing strategies for the medicinal management of marijuana dependence. No such strategies exist at present , despite the fact that pharmacotherapy—alone or in combination with behavioral therapy—is considered a primary treatment option for drug dependence when abuse prevention fails . Several basic questions, which are relevant to the pharmacotherapy of marijuana dependence, remain unanswered. For example, while it is clear that D9 -THC acts by hijacking the brain endocannabinoid system, its impact on the various components of this system—synthetic and catabolic enzymes, transporters, and receptors—is still largely undefined. Does D9 -THC produce rapid adaptive changes in neuronal endocannabinoid signaling, as recent evidence indicates ? And, if so, do such changes contribute to the pharmacological actions of the drug? Does prolonged exposure to D9 -THC cause stable alterations in endocannabinoid signaling? And, if so, do such alterations contribute to marijuana dependence and, most importantly, can they be safely reversed to restore normality? Answering these questions may not only help develop effective therapeutic strategies for marijuana dependence, but in light of the broad roles played by the endocannabinoid system in the control of brain reward processes , might also shed new light on fundamental mechanisms of drug addiction. To accomplish this task, it seems important to move forward in two convergent directions: the molecular characterization of endocannabinoid signaling, much of which is still uncharted; and the development of pharmacological agents that interfere with specific components of this system. In the present review, I outline recent progress made in these directions, specifically focusing on endocannabinoid deactivation, and discuss some of the challenges lying ahead.Anandamide was the first endocannabinoid sub stance to be isolated and structurally characterized . Its formationinneural cells is thought to require two enzymatic steps, which are illu strated in Fig. 1.This reaction, which is mediated by a unique D-type phospholipase , produces anandamide and phosphatidic acid, which is recycled to produce other glycerol-containing phospholipids. The cellular stores of NAPE are small, but canbe refilled by an N-acyltransferase activity, which catalyzes the intermolecular passage of anarachidonic acid group from the sn-1 positionof phosphatidylcholine to the head group of phos phatidylethanolamine . Incultures of rat cortical neurons, NAT activity is controlled by two intracellular second messengers: Ca2+, which is required to activate the enzyme, and cyclic 30 , 50 -adeno sine monophosphate , which stimulates protein kinase A-dependent protein phosphorylation and, via an unknown mechanism, enhances NAT activity .