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Background: Depressive disorders affect approximately 280 million globally, with many finding treatments ineffective or limited by side effects. Growing evidence suggests that psychedelic therapies may help alleviate depressive symptoms. Among these, lysergic acid diethylamide (LSD) microdosing shows promise for major depressive disorder (MDD). However, research on LSD microdosing in clinical populations remains limited. Objectives: This study aimed to understand the experiences of individuals participating in an open-label trial of LSD microdosing for MDD. Design: Open-label pilot trial in target population (MDD; phase IIa). Methods: Seventeen participants with MDD completed an 8-week LSD microdosing regimen, dosing twice weekly. Following the intervention, participants underwent semi-structured interviews regarding their experiences. Data were analysed using thematic analysis. Results: Themes were grouped into five categories: enhanced self-determination, increased connectedness, improved cognitive processing, better emotional well-being, and negative effects. Conclusion: Reported effects appeared to reinforce one another; that is, self-determination led to feeling more connected, which enhanced cognitive processing and ultimately improved emotional well-being and reduced depressive symptoms. However, this effect was not universal; some individuals reported negative effects or no significant improvement from microdosing LSD. This variability may be due to individual differences in response, insufficient dosage, or the treatment’s lack of effectiveness for some individuals. The presence of side effects highlights the need for a careful titration protocol, while the lack of symptom improvement in some cases reinforces that microdosing is not a guaranteed solution, and expectations should remain realistic. The absence of a placebo control represents a key limitation as it precludes attribution of observed changes specifically to LSD. Trial registration: ANZCTR, ACTRN12623000486628. Registered on 12 May 2023 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385758). Plain language summary Depression affects millions of people worldwide, and many find that current treatments either don’t work or have unwanted side effects. Recent research suggests that psychedelic substances, like LSD, may help improve mood when used carefully small amounts. This practice is known as LSD microdosing. Despite growing interest, there is very little controlled research on how LSD microdosing affects people with depression. In this study, we invited 17 adults with depression to take very low doses of LSD twice a week for eight weeks. After the study, we asked them about their experiences to understand how microdosing affected them. Participants reported a range of experiences. Many described feeling more motivated to engage in daily activities, a stronger sense of connection with others, clearer thinking, new personal insights, and overall improvements in emotional well-being. The improvements participants described often seemed to build on each other—for example, feeling more connected encouraged them to take part in more activities, which then helped them feel mentally clearer and emotionally better. However, not everyone benefited. Some participants reported negative experiences or no noticeable improvement, suggesting that microdosing may not work for everyone. The study also did not include a placebo comparison, so it is unclear whether the changes were due specifically to LSD. Overall, these findings suggest that LSD microdosing may offer some people with depression new ways to feel more connected, motivated, and emotionally balanced. At the same time, careful monitoring is important due to potential side effects, and expectations should remain realistic.

RationaleThe 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.ObjectivesThe objective of this study is to review available data regarding cannabis/cannabinoid co-use or exposure on amphetamine-related outcomes.MethodsTowards 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.ResultsTwenty-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).ConclusionsWhile 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.

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.

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.

Background Major depressive disorder (MDD) poses a significant global health burden with available treatments limited by inconsistent efficacy and notable side effects. Classic psychedelics, including lysergic acid diethylamide (LSD), have garnered attention for their potential in treating psychiatric disorders. Microdosing, the repeated consumption of sub-hallucinogenic doses of psychedelics, has emerged as a self-treatment approach for depression within lay communities. Building upon preliminary evidence and the successful completion of an open-label pilot trial of microdosing LSD for depression (LSDDEP1), this protocol outlines a phase 2b randomised controlled trial (LSDDEP2). The main objective of LSDDEP2 is to assess the modification of depressive symptoms, measured by the Montgomery–Åsberg Depression Rating Scale (MADRS), following a regimen of LSD microdoses versus placebo. Methods This is a randomised, double-dummy, triple-blind, active placebo-controlled, parallel groups trial of LSD microdosing in patients meeting DSM-5 criteria for major depressive disorder. Participants will undergo an 8-week LSD microdosing regimen using the titratable MB-22001 formulation taking two doses a week. All doses will be self-administered at home and will be titratable from 4 to 20 μg based on subjective perception and tolerability. In addition to depression symptoms, outcome will include psychiatric and personality inventories, sleep and activity tracking, electroencephalography (EEG), blood biomarkers, semi-structured interviews, and safety (e.g. adverse event, laboratory exam) measures. Discussion This study will be the first randomised controlled trial to administer controlled microdoses of LSD for treatment of MDD in participants’ naturalistic environment. The measures included are designed to assess the drug’s safety, mechanism, and treatment efficacy over placebo in this population. The results of this study will be important for assessing the viability of psychedelic microdosing as an additional treatment option and for informing the direction of future clinical trials. Trial registration ANZCTR, ACTRN12624000128594. Prospectively Registered on 13 February 2024.

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.

Undertakes a critical review and assessment of 10 of the Bill’s main regulation components, based on evidence from and experiences with cannabis policy elsewhere as well as other substance policy areas : political promises; age of use/access; places of use; penalties for underage use; ‘home-growing’; retail distribution; licensed production; products available; new/remaining offences; research and monitoring. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.

RationaleSmoking-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.ObjectivesTo establish which factors predict smoking cessation in people who reported quitting or reducing smoking following ayahuasca consumption.MethodsA 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.ResultsA 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.ConclusionsOur 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.