Can old drugs learn new tricks? Achieving registration and public subsidy listing for off-patent medicines with novel therapeutic applications.

With the increasing costs of drug development, repurposing of low-cost medicines for new indications has never been more important. However, there are multiple barriers to repurposing, particularly for off-patent medicines, and limited incentives for the pharmaceutical industry to sponsor registration and public subsidy listing. Here, we explore these barriers and their consequences and provide examples of successful repurposing strategies.

Medicinal psychedelics for mental health and addiction: Advancing research of an emerging paradigm.

The medical use of psychedelic substances (e.g. psilocybin, ayahuasca, lysergic acid diethylamide and 3,4-methylenedioxymethamphetamine) is attracting renewed interest, driven by a pressing need for research and development of novel therapies for psychiatric disorders, as well as promising results of contemporary studies. In this Viewpoint, we reflect upon the 'Clinical Memorandum on Psychedelics' recently released by the Royal Australian and New Zealand College of Psychiatrists and note subsequent developments including the application for down-scheduling of psilocybin and 3,4-methylenedioxymethamphetamine presently being considered by the Therapeutic Goods Administration and approvals for access via the Special Access Scheme. We suggest that this field is worthy of rigorous research to assess potential benefits, address safety parameters and clarify therapeutic mechanisms. To this end, we outline recent research findings, provide an overview of current knowledge relating to mechanisms of action and discuss salient aspects of the psychedelic-assisted psychotherapy treatment model. The sum of this research points towards medicinal psychedelics as a potential new class of psychiatric treatments when used within a medically supervised framework with integrated psychotherapeutic support. However, before widespread translation into clinical use can occur, appropriately designed and sufficiently powered trials are required to detect both potential positive and negative outcomes. Unique safety and regulatory challenges also need to be addressed. As for any new medical therapy, psychedelic research needs to be conducted in a rigorous manner, through the dispassionate lens of scientific enquiry. Carte blanche availability to practitioners, without specific protocols and appropriate training, would be potentially harmful to individuals and detrimental to the field.

Psilocybin-assisted therapy for depression: How do we advance the field?

In the quest for new treatment options for depression, attention is being paid to the potential role of psychedelic drugs. Psilocybin is of particular interest given its mechanism of action, its benefits in early trials and its relatively low side effects burden. This viewpoint outlines a number of key issues that remain to be elucidated about its potential use in the clinical environment, including clarification of the profile of people most likely to benefit and those who might experience adverse effects, longer-term outcomes and the role of psychotherapeutic input alongside the drug itself. There are also opportunities to understand better, the neurobiology underpinning its effects.

Mobile Apps to Reduce Tobacco, Alcohol, and Illicit Drug Use: Systematic Review of the First Decade.

BACKGROUND: Mobile apps for problematic substance use have the potential to bypass common barriers to treatment seeking. Ten years following the release of the first app targeting problematic tobacco, alcohol, and illicit drug use, their effectiveness, use, and acceptability remains unclear. OBJECTIVE: This study aims to conduct a systematic literature review of trials evaluating mobile app interventions for problematic tobacco, alcohol, and illicit drug use. METHODS: The review was conducted according to recommended guidelines. Relevant databases were searched, and articles were included if the mobile app study was a controlled intervention trial and reported alcohol, tobacco, or illicit drug consumption as outcomes. RESULTS: A total of 20 studies met eligibility criteria across a range of substances: alcohol (n=11), tobacco (n=6), alcohol and tobacco (n=1), illicit drugs (n=1), and illicit drugs and alcohol (n=1). Samples included the general community, university students, and clinical patients. The analyzed intervention sample sizes ranged from 22 to 14,228, and content was considerably diverse, from simple stand-alone apps delivering self-monitoring or psychoeducation to multicomponent apps with interactive features and audio content, or used as adjuncts alongside face-to-face treatment. Intervention duration ranged from 1 to 35 weeks, with notifications ranging from none to multiple times per day. A total of 6 of the 20 app interventions reported significant reductions in substance use at post or follow-up compared with a comparison condition, with small to moderate effect sizes. Furthermore, two other app interventions reported significant reductions during the intervention but not at post treatment, and a third reported a significant interaction of two app intervention components. CONCLUSIONS: Although most app interventions were associated with reductions in problematic substance use, less than one-third were significantly better than the comparison conditions at post treatment. A total of 5 out of the 6 apps that reported intervention effects targeted alcohol (of those, one targeted alcohol and illicit drugs and another alcohol and tobacco) and 1 targeted tobacco. Moreover, 3 out of 6 apps included feedback (eg, personalized) and 2 had high risk of bias, 1 some risk, and 3 low risk. All 6 apps included interventions of 6 weeks or longer. Common study limitations were small sample sizes; risk of bias; lack of relevant details; and, in some cases, poorly balanced comparison conditions. Appropriately powered trials are required to understand which app interventions are most effective, length of engagement required, and subgroups most likely to benefit. In sum, evidence to date for the effectiveness of apps targeting problematic substance use is not compelling, although the heterogeneous comparison conditions and trial designs across studies limit the ability to compare efficacy between apps. We discuss potential approaches that can help ascertain whether the promise of mobile app interventions for problematic substance use can be fulfilled.

Is microdosing a placebo? A rapid review of low-dose LSD and psilocybin research.

Some recent research and commentary have suggested that most or all the effects reported by people who microdose psychedelics may be explained by expectations or placebo effects. In this rapid review, we aimed to evaluate the strength of evidence for a placebo explanation of the reported effects of microdosing. We conducted a PubMed search for all studies investigating psychedelic microdosing with controlled doses and a placebo comparator. We identified 19 placebo-controlled microdosing studies and summarised all positive and null findings across this literature. Risk of bias was assessed using the Cochrane risk-of-bias tool for randomised trials. The reviewed papers indicated that microdosing with LSD and psilocybin leads to changes in neurobiology, physiology, subjective experience, affect, and cognition relative to placebo. We evaluate methodological gaps and challenges in microdosing research and suggest eight reasons why current claims that microdosing is predominately a placebo are premature and possibly wrong: (1) there have been only a small number of controlled studies; (2) studies have had small sample sizes; (3) there is evidence of dose-dependent effects; (4) studies have only investigated the effects of a small number of doses; (5) the doses investigated may have been too small; (6) studies have looked only at non-clinical populations; (7) studies so far have been susceptible to selection bias; and (8) the measured impact of expectancy is small. Considering the available evidence, we conclude that it is not yet possible to determine whether microdosing is a placebo.

The psychedelic call: analysis of Australian Poisons Information Centre calls associated with classic psychedelics.

INTRODUCTION: The global use of certain classical psychedelics has increased in recent years, but little is known about their spectrum of toxicity within Australia. We aim to describe calls to New South Wales Poisons Information Centre relating to exposures to classical psychedelics including lysergic acid diethylamide, psilocybin, N,N-dimethyltryptamine, ayahuasca, mescaline and ibogaine. METHODS: This is a retrospective observational study of calls to New South Wales Poisons Information Centre between January 2014 and December 2022. We identified exposures to classical psychedelics within New South Wales Poisons Information Centre database and measured the annual number of exposures, source of call (hospital, health care worker, member of the public), co-ingested substances, clinical features and advice given. RESULTS: There were 737 calls related to relevant psychedelic exposures; 352 (47.8 per cent) to lysergic acid diethylamide, 347 (47.0 per cent) to psilocybin, 28 (3.8 per cent) to N,N-dimethyltryptamine, 4 (0.5 per cent) to ayahuasca, 4 (0.5 per cent) to mescaline and 2 (0.3 per cent) to ibogaine. Cases were predominantly male (77.2 per cent) and aged between 20 and 74 years (65.6 per cent). Psychedelic calls more than doubled from 45 in 2014 to 105 in 2022 and 625 (85 per cent) of all calls were either from or referred to hospital. Co-ingestion of psychedelics with another substance occurred in 249 (33.8 per cent) of calls and the most frequent clinical features related to single substance psychedelic exposures were hallucinations (27.6 per cent), gastrointestinal symptoms (21.7 per cent) and tachycardia (18.1 per cent). Seizures occurred in 2.9 per cent of single substance psychedelic exposures. DISCUSSION: Increasing incidence of psychedelic exposure calls, including those reporting significant toxicity, likely reflects increasing community use. This may in part be driven by increasing interest in psychedelic assisted psychotherapy trials subsequently increasing public awareness. CONCLUSION: Relatively high poisoning severity contrasts with safety within clinical trials of psychedelic assisted psychotherapy that may relate to the uncontrolled nature of community use which is mitigated within clinical trial environments. Education about safe use may be useful.

How psychedelic-assisted therapy works for depression: expert views and practical implications from an exploratory Delphi study.

As investigations into the efficacy of psychedelic-assisted psychotherapy to treat depression continue, there is a need to study the possible mechanisms of action that may contribute to the treatment's antidepressant effects. Through a two-round Delphi design, the current study investigated experts' opinions on the psychological mechanisms of action associated with the antidepressant effects of psychedelic-assisted psychotherapy and the ways such mechanisms may be promoted through the preparation, dosing, and integration components of treatment. Fourteen and fifteen experts, including both clinical psychedelic researchers and therapists, participated in Round 1 and Round 2 of the study, respectively. Thematic analysis identified nine important or promising 'mechanistic themes' from Round 1 responses: psychological flexibility, self-compassion, mystical experiences, self-transcendence, meaning enhancement, cognitive reframing, awe, memory reconsolidation and ego dissolution. These mechanisms were presented back to experts in Round 2, where they rated 'psychological flexibility' and 'self-compassion' to be the most important psychological mechanisms in psychedelic-assisted psychotherapy for depression. Strategies or interventions recommended to promote identified mechanisms during the preparation, dosing, and integration components of treatment were nonspecific to the endorsed mechanism. The findings from this study provide direction for future confirmatory mechanistic research as well as provisional ideas for how to support these possible therapeutic mechanisms.

Exploring psilocybin-assisted psychotherapy in the treatment of methamphetamine use disorder.

Methamphetamine use disorder is a chronic relapsing condition associated with substantial mental, physical, and social harms and increasing rates of mortality. Contingency management and psychotherapy interventions are the mainstays of treatment but are modestly effective with high relapse rates, while pharmacological treatments have shown little to no efficacy. Psilocybin-assisted psychotherapy is emerging as a promising treatment for a range of difficult-to-treat conditions, including substance use disorders; however, no studies have yet been published looking at psilocybin-assisted psychotherapy in the treatment of methamphetamine use disorder. Here we review the rationale for psilocybin-assisted psychotherapy as a potential treatment for this indication, and describe practical considerations based on our early experience designing and implementing four separate clinical trials of psilocybin-assisted psychotherapy for methamphetamine use disorder.

The emerging science of microdosing: A systematic review of research on low dose psychedelics (1955-2021) and recommendations for the field.

The use of low doses of psychedelic substances (microdosing) is attracting increasing interest. This systematic review summarises all empirical microdosing research to date, including a set of infrequently cited studies that took place prior to prohibition. Specifically, we reviewed 44 studies published between 1955 and 2021, and summarised reported effects across six categories: mood and mental health; wellbeing and attitude; cognition and creativity; personality; changes in conscious state; and neurobiology and physiology. Studies showed a wide range in risk of bias, depending on design, age, and other study characteristics. Laboratory studies found changes in pain perception, time perception, conscious state, and neurophysiology. Self-report studies found changes in cognitive processing and mental health. We review data related to expectation and placebo effects, but argue that claims that microdosing effects are largely due to expectancy are premature and possibly wrong. In addition, we attempt to clarify definitional inconsistencies in the microdosing literature by providing suggested dose ranges across different substances. Finally, we provide specific design suggestions to facilitate more rigorous future research.

The psychological processes of classic psychedelics in the treatment of depression: a systematic review protocol.

BACKGROUND: There is currently renewed interest in the use of psychedelic therapy in the treatment of psychiatric disorders, including depression. The proposed systematic review will aim to identify, evaluate and summarise the psychological processes of change underlying psychedelic therapy for depression in the current literature and consider the implications these processes may have on the psychotherapy component of treatment. METHODS: Scopus, PsycINFO, PubMed and Web of Science databases will be searched using relevant terms. Studies will be included if they discuss the use of a classic psychedelic to treat depression symptomology in an adult population and report or propose psychological processes responsible for depression symptom change. Two authors will independently screen articles, complete quality assessment tools and conduct data extraction. Empirical and non-empirical research will be extracted and synthesised separately. A narrative synthesis approach will be used to report psychological processes identified in the literature. DISCUSSION: This systematic review will be the first to collate available evidence on the psychological processes associated with psychedelic therapy for depression. The preliminary nature of this research field is expected to result in the review having several limitations, namely heterogeneity between studies and the inclusion of limited empirical research. We intend for this review to present the current state of the literature, identify gaps and generate candidate variables that warrant further investigation. SYSTEMATIC REVIEW: PROSPERO CRD42020197202.

Alcohol-Involved Family and Domestic Violence Reported to Police in Australia.

Family and domestic violence (FDV) is a significant social issue that causes major harm across Australia. Alcohol has been identified as a contributing factor to FDV, and as such increased understanding of the role of alcohol in police-reported FDV incidents may provide the basis for developing specific clinical and forensic approaches. This study aims to identify the key correlates of alcohol-related FDV within police-reported FDV incidence. Data sourced from several states and territories across Australia were used to profile demographic and personal factors involved in police-reported FDV incidents, and to identify the types of incidents involving alcohol. For each state, three separate binary regressions were conducted for family violence, intimate partner violence, and FDV incidents in which alcohol was involved. Between 24% and 54% of FDV incidents reported to police were classified as alcohol-related. Although there appeared to be an association between relative socioeconomic disadvantage and an incident being alcohol-related, this association varied across states. Where victim and offender data were available, offenders were significantly more likely to be alcohol-affected than victims. Alcohol-related FDV incidents were also twice as likely to involve severe physical violence including injuries that were life threatening, as well as an increased likelihood of recidivism. This study demonstrates that alcohol plays a substantial role in police-reported FDV across Australia. It also demonstrates that other factors such as drug use, breach of orders, and repeat offending are associated with alcohol involvement across family violence and intimate partner violence.

Combining Psychedelic and Mindfulness Interventions: Synergies to Inform Clinical Practice.

Psychedelic and mindfulness interventions have been shown to improve mental ill-health and wellbeing, with a range of clinical processes and effects in common. However, each appear to contain specific challenges in the context of mental health treatment. In this Perspective, we focus on a set of distinct affordances, "useful differences", within psychedelic and mindfulness interventions that might address common challenges within the other intervention. Accordingly, we propose a set of applied synergies, indicating specific ways in which these two promising interventions might be combined for greater benefit. Metaphorically, on the journey toward mental health and wellbeing, we propose that psychedelic treatments may serve the role of Compass (initiating, motivating, and steering the course of mindfulness practice), with mindfulness interventions serving the role of Vehicle (integrating, deepening, generalizing, and maintaining the novel perspectives and motivation instigated by psychedelic experience). We outline a set of testable hypotheses and future research associated with the synergistic action of psychedelic and mindfulness interventions toward improved clinical outcomes.

The Role of Illicit Drug Use in Family and Domestic Violence in Australia.

Drug use has been shown to interact in complex ways with the occurrence and prevalence of family and domestic violence (FDV), with illicit drug use being associated with an increased risk for FDV. The current study aims to extend upon the literature by investigating the role of illicit drugs in intimate partner violence (IPV), family violence (FV), and other violence (violence between people other than partners or family) within a representative Australian sample (n = 5,118). Participants were recruited through an online survey panel and completed an online self-report survey assessing the role of alcohol and other drugs on violence, with a specific focus on FDV. Binary logistic regression showed that respondents who reported having used any illicit drug in the past 12 months (with or without alcohol use) had over three times the odds of experiencing any violence in the past 12 months (OR = 3.18, 95% confidence interval (CI) = [2.25, 4.48]) compared with those not using illicit drugs. Furthermore, drug involvement in FDV (IPV or FV) was significantly more likely than other violent incident types (OR = 1.65, 95% CI = [1.25, 2.19]). For the most recent FDV incident, age group was the only significant demographic predictor of drug involvement at this incident; younger age groups were over twice as likely to report drug involvement than those over 65 years of age. Drug involvement at the most recent FDV incident was also associated with over twice the odds of injury (OR = 2.38, 95% CI = [1.67, 3.38]) and significantly greater negative life impact. The findings that drug use increases both the risk for and impact of FDV indicate the need for policy that advocates for interventions addressing both drug use and violence in combination.

Situational Characteristics Uniquely Associated With Children's Exposure to Intimate Partner Violence.

Exposure to parental violence can have devastating consequences for children, including significant personal, social, and academic problems. The present study determined the situational factors that are associated with children's exposure to intimate partner violence (IPV) incidents. To examine whether these factors were unique to child witnesses' presence at IPV incidents, we also determined the factors that are associated with children's exposure to family violence (FV) and other family member witnesses' exposure to IPV incidents. Participants responded to an online panel survey investigating the role of alcohol and other drugs in family and domestic violence incidents in Australia. Nine hundred fifty-two respondents reported an IPV incident and 299 reported an FV incident; they provided details about their most recent incident. Results showed that child witnesses were more likely to be present during IPV incidents if the incident took place at home (odds ratio [OR] = 3.10), if a similar incident had occurred previously (OR = 1.66), if drugs were involved (OR = 1.60), and if a police report was made (OR = 2.61). There was some overlap with the other witness and violence combinations: The presence of a police report also predicted child witnesses' presence at FV incidents, and a home location also predicted other family member witnesses' presence at IPV incidents. These results enhance our understanding of the situations in which children might witness IPV incidents; future research is needed to determine whether these situational factors can be used to judge risk.

Translating Psychedelic Therapies From Clinical Trials to Community Clinics: Building Bridges and Addressing Potential Challenges Ahead.

Research exploring the potential of psychedelic-assisted therapies to treat a range of mental illnesses is flourishing, after the problematic sociopolitical history of psychedelics led to the shutdown of clinical research for almost 40 years. Encouraged by positive results, clinicians and patients are now hopeful that further interruptions to research will be avoided, so that the early promise of these therapies might be fulfilled. At this early stage of renewed interest, researchers are understandably focusing more on clinical trials to investigate safety and efficacy, than on longer-term goals such as progression to community practice. Looking to identify and avoid potential pitfalls on the path to community clinics, the authors, a group of Australian clinicians and researchers, met to discuss possible obstacles. Five broad categories of challenge were identified: 1) inherent risks; 2) poor clinical practice; 3) inadequate infrastructure; 4) problematic perceptions; and 5) divisive relationships and fractionation of the field. Our analysis led us to propose some strategies, including public sector support of research and training to establish best practice and optimize translation, and funding to address issues of equitable access to treatment. Above all, we believe that strategic planning and professional cohesion will be crucial for success. Accordingly, our key recommendation is the establishment of a multidisciplinary advisory body, broadly endorsed and representing all major stakeholders, to guide policy and implementation of psychedelic-assisted therapies in Australia. Although these challenges and strategies are framed within the Australian context, we sense that they may generalize to other parts of the world. Wherever they apply, we believe that anticipation of potential difficulties, and creative responses to address them, will be important to avoid roadblocks in the future and keep the "psychedelic renaissance" on track.

Rethinking Therapeutic Strategies for Anorexia Nervosa: Insights From Psychedelic Medicine and Animal Models.

Anorexia nervosa (AN) has the highest mortality rate of any psychiatric disease, yet available pharmacological treatments are largely ineffective due, in part, to an inadequate understanding of the neurobiological drivers that underpin the condition. The recent resurgence of research into the clinical applications of psychedelic medicine for a range of mental disorders has highlighted the potential for classical psychedelics, including psilocybin, to alleviate symptoms of AN that relate to serotonergic signaling and cognitive inflexibility. Clinical trials using psychedelics in treatment-resistant depression have shown promising outcomes, although these studies are unable to circumvent some methodological biases. The first clinical trial to use psilocybin in patients with AN commenced in 2019, necessitating a better understanding of the neurobiological mechanisms through which psychedelics act. Animal models are beneficial in this respect, allowing for detailed scrutiny of brain function and behavior and the potential to study pharmacology without the confounds of expectancy and bias that are impossible to control for in patient populations. We argue that studies investigating the neurobiological effects of psychedelics in animal models, including the activity-based anorexia (ABA) rodent model, are particularly important to inform clinical applications, including the subpopulations of patients that may benefit most from psychedelic medicine.

Longitudinal Substance Use and Biopsychosocial Outcomes Following Therapeutic Community Treatment for Substance Dependence.

The Therapeutic Community (TC) model is considered an effective treatment for substance dependence, particularly for individuals with complex presentations. While a popular approach for this cohort across a number of countries, few studies have focussed on biopsychosocial and longer-term outcomes for this treatment modality. This study reports on substance use, dependence, and biopsychosocial outcomes up to 9 months post-exit from two TC sites. METHODS: A longitudinal cohort study (n = 166) with two follow-up time points. Measures included substance use, dependence, subjective well-being, social functioning, and mental and physical health. Generalized Linear Models were employed to assess change over time. RESULTS: At 9 months, 68% of participants reported complete 90-day drug abstinence. Alcohol frequency and quantity were reduced by over 50% at 9 months, with 32% of the sample recording 90-day abstinence at 9 months. Both alcohol and drug dependence scores were reduced by over 60%, and small to medium effect sizes were found for a range of psychosocial outcomes at 9 months follow-up, including a doubling of wellbeing scores, and a halving of psychiatric severity scores. Residents who remained in the TC for at least 9 months reported substantially better outcomes. CONCLUSIONS: With notably high study follow-up rates (over 90% at 9 months post-exit), these data demonstrate the value of the TC model in achieving substantial and sustained improvements in substance use and psychosocial outcomes for a cohort with severe substance dependence and complex presentations. Implications for optimal length of stay are discussed.

Alcohol use in family, domestic and other violence: Findings from a cross-sectional survey of the Australian population.

INTRODUCTION AND AIMS: The link between alcohol and experience of violence is well-documented, but there is a paucity of empirical research on the role of alcohol specifically in family and domestic violence (FDV) in Australia. The aim of the current study was to describe the relationship between alcohol use and FDV in the Australian population, and to examine key differences between three different types of violence: family violence, intimate partner violence (IPV) and other violence. DESIGN AND METHODS: An online panel survey was conducted using a stratified random sampling design. RESULTS: In total, 5118 respondents were included, of whom 44.5% reported experiencing violence in their lifetime, and 6.0% reported recent (past year) experience of violence. Recent violent incidents were comprised of IPV (41.8%), family violence (13.1%) and other violence (45.1%). Approximately one-third of all violent incidents experienced (either as a victim or perpetrator) were alcohol-related, and 37.8% of respondents who experienced IPV and 27.8% of those who experienced family violence reported past year heavy-episodic drinking. Alcohol use was associated with higher rates of physical violence and injury at IPV incidents. Alcohol consumed at IPV incidents was most often purchased from a supermarket liquor store (37.0%) and consumed at the respondent's home, regardless of the distance between the purchase location and incident location. DISCUSSIONS AND CONCLUSIONS: This study found that alcohol is frequently involved in FDV incidents, particularly IPV. Alcohol use was associated with a higher chance of physical violence and of injury at IPV incidents.

Ecological momentary assessment of drinking in young adults: An investigation into social context, affect and motives.

INTRODUCTION: Daily assessment studies have examined how day specific factors, such as affect, social context, and drinking motives, alongside dispositional drinking motives, predict young adults' drinking. However, these studies did not examine how the interplay between drinking motives (dispositional and day specific) and multiple features of the drinking situation predict drinking with respect to either the initial decision to drink or the quantity of alcohol consumed. Ecological momentary assessment (EMA) via smartphone technology, enables us to address this gap by evaluating to what extent dispositional drinking motives and day specific factors are associated with: a) the initiation of drinking episodes and; b) the quantity of alcohol consumed. METHODS: Participants were 83 young adults (63 female) aged 18 to 30 (M = 21.42, SD = 3.09) who resided in Australia and participated in an EMA study for 21 days via their smartphone. On a daily basis, participants received three random-interval prompts that measured momentary affect, drinking motives, social context (e.g., people present in the social context and if these individuals are drinking), and alcohol use. RESULTS: A multilevel hurdle analysis found that young adults were more likely to both initiate a drinking episode and consume a higher quantity of alcohol if they were surrounded by other people who were drinking and were motivated to drink to conform to the reference group. CONCLUSIONS: This study is the first of its kind to demonstrate that different drinking behaviors (i.e., initiation and quantity of alcohol consumed) are associated with a similar set of predictors. Drinking-based interventions that address these risk factors could effectively reduce risky drinking as it would intervene on both the decision to initiate alcohol use, and the decision to continue drinking.