MDMA-assisted psychotherapy for post-traumatic stress disorder: The devil is in the detail.

Recent years have seen escalating media, public and scientific interest in psychedelic medicine. Australia and New Zealand have been late to this research; however, in the past 2 years, rapid developments suggest that this is changing. Here, we argue for the need to critically review existing evidence in this field to guide future directions. We focus on (±)3,4-methylenedioxymethamphetamine-assisted psychotherapy for post-traumatic stress disorder, currently the most advanced area of clinical psychedelic research. Food and Drug Administration approval of this approach is likely in 2023, based on a series of promising findings. We provide a detailed overview of Phase 2 and 3 studies published to date. We identify several concerns related to this body of evidence, including methodological/design limitations and broader factors - such as robust involvement of advocacy groups in research and reliance on non-government financing leading to simplistic public messaging - that compound the methodological issues identified. We propose steps for future improvement, including the need for large, high-quality, independent efficacy trials with design enhancements, effectiveness trials and for researchers to consider their own engagement with media and public messaging around these modalities. We argue that, notwithstanding promising findings to date, rigorous and dispassionate science is needed to move the field forward and safeguard the welfare of participants.

Extinction and drug-induced reinstatement of cocaine seeking following self-administration or conditioned place preference in adolescent and adult rats.

Adolescence marks a particularly vulnerable period to developing substance use disorders, and people who start using drugs in adolescence are more likely to relapse. A limited number of studies have investigated age difference in relapse following re-exposure to the drug after a period of abstinence. Using a cocaine self-administration paradigm, we showed no age difference in acquisition or extinction of self-administration. Interestingly, adolescent rats displayed impaired cocaine-primed reinstatement of cocaine seeking. Using the same dose as that self-administered in the first experiment, we then investigated age differences in acquisition and extinction of conditioned place preference, as well as locomotor sensitization. While there were no differences in locomotor activity or acquisition of preference, adolescents failed to extinguish their preference, even when the number of extinction sessions was doubled from what adults received. Taken together, these results suggest that while cocaine has similar rewarding and reinforcing effects regardless of age, adolescents may attribute stronger salience to the drug-associated context. In addition, re-exposure to cocaine itself may not be a strong relapse trigger in adolescence. Overall, these findings suggest that we should focus more on alleviating drug-context salience compared to re-exposure to substance in order to reduce relapse of drug seeking in adolescents.

Investigating the role of dopamine receptor- and parvalbumin-expressing cells in extinction of conditioned fear.

The present study examined the pattern of activation of neurons that express dopamine receptors 1 and 2 (D1R and D2R), and parvalbumin (PV) in mice that underwent extinction of a fear memory. Adult male transgenic mice expressing D1R or D2R tagged with green fluorescent protein (GFP) were conditioned with 6 tone-shock pairings. The following day they were randomly divided into one of four experimental groups: extinction, retrieval, context or handled. Extinction groups were exposed to 45 tone presentations, retrieval groups were exposed to 5 tone presentations and the context groups were exposed to the chamber without any tones. Ninety minutes following their assigned treatment, mice were perfused and brain tissue processed for Fos/GFP/PV immunohistochemistry. Quantification of immunoreactivity revealed that extinction resulted in changes in the infralimbic cortex including increased Fos expression and a decrease in the number of D2R+ cells compared to all other groups. Conversely, fear memory retrieval resulted in increased activation of D2R+ cells in the prelimbic cortex compared to all other groups. Additional changes were observed in the extinction and retrieval groups that were different to the handled group, but not to the context group, which highlights that there is overlapping neurocircuitry between extinction and retrieval of fear memory, as well as with context exposure. These results provide novel insights into the roles of specific dopamine receptor subtypes, which will be valuable for informing future research that aims to strengthen extinction learning via dopaminergic mechanisms.

Side-effects of mdma-assisted psychotherapy: a systematic review and meta-analysis.

Evidence suggests that MDMA-assisted psychotherapy (MDMA-AP) has therapeutic potential for treatment of psychiatric illness. We conducted the first comprehensive systematic review and meta-analysis of the side effects of MDMA-AP across indications. We also assessed the quality of side effects-reporting in published trials of MDMA-AP. PubMed, EMBASE, PsycINFO, MEDLINE and Cochrane Central Register of Controlled Trials (CENTRAL) were systematically searched. Phase 2 and 3 MDMA-AP studies were included; Phase 1 studies, which assessed MDMA without psychotherapy, were not. Quality of side effects-reporting was assessed against the CONSORT Harms 2022 guidelines. We also compared numbers of adverse events reported in publications to those recorded in ClinicalTrial.gov registers. Thirteen studies were included, with eight contributing to the meta-analysis. In Phase 2 studies, MDMA-AP was associated with increased odds of any side effect during medication sessions (OR = 1.67, 95%CI (1.12, 2.49)) and in the 7 days following (OR = 1.59, 95%CI (1.12, 2.24)) relative to control conditions. In Phase 3 studies, MDMA-AP was associated with increased odds of any adverse event during the treatment period relative to placebo-assisted psychotherapy (OR = 3.51, 95%CI (2.76, 4.46)). The majority of RCTs were rated as having high risk of bias. Certainty of the evidence was rated as very low to moderate according to the GRADE framework. No included RCT had adequate adherence to the CONSORT Harms 2022 recommendations and reporting rates were also low. Compared to placebo, MDMA-AP was associated with increased odds of side effects, which were largely transient and mild or moderate in severity. However, identified limitations in existing evidence indicate that further investigation is needed to better characterize the safety profile of MDMA-AP and guide implementation.

A systematic review and meta-analysis of health, functional, and cognitive outcomes in young people who use methamphetamine.

Methamphetamine use typically starts in adolescence, and early onset is associated with worse outcomes. Yet, health, functional, and cognitive outcomes associated with methamphetamine use in young people are not well understood. The aim of this study was to comprehensively assess the evidence on health, functional, and cognitive outcomes in young people (10-25 years-old) who use methamphetamine. Sixty-six studies were included. The strongest association observed was with conduct disorder, with young people who use methamphetamine some 13 times more likely to meet conduct disorder criteria than controls. They were also more likely to have justice system involvement and to perpetrate violence against others. Educational problems were consistently associated with youth methamphetamine use. The cognitive domain most reliably implicated was inhibitory control. Key limitations in the literature were identified, including heterogenous measurement of exposure and outcomes, lack of adequate controls, and limited longitudinal evidence. Outcomes identified in the present review - suggesting complex and clinically significant behavioural issues in this population - are informative for the development of future research and targeted treatments.

Clinical Effectiveness of Muscarinic Receptor-Targeted Interventions in Neuropsychiatric Disorders: A Systematic Review.

BACKGROUND: For decades, treatment of mood disorders, psychoses, anxiety and dementia have been confounded by limited efficacy and high rates of treatment resistance. Preclinical and clinical evidence have highlighted disruption of cholinergic signalling in several neuropsychiatric conditions and examined intervention strategies including acetylcholinesterase inhibitors and nicotinic receptor-targeted intervention. However, the effectiveness of these approaches is often curtailed by on-target side effects. Post mortem studies implicate muscarinic receptor dysregulation in neuropsychiatric pathophysiology; therefore, we conducted a systematic review and meta-analysis to investigate the therapeutic efficacy and safety of muscarinic receptor-targeted interventions in adults with neuropsychiatric disorders. METHODS: PubMed, EMBASE, PsycINFO, EBSCO and Web of Science were searched using relevant keywords from database inception to 7 August 2022. Randomised, double-blind, placebo-controlled studies were included if they investigated the effect of muscarinic receptor-targeted intervention in adults with a diagnosis of a neuropsychiatric disorder and were published in English. A narrative synthesis approach was adopted to describe the findings. Wherever three or more studies with a similar intervention were available, effect sizes were calculated, and a meta-analysis was performed. Cochrane risk-of-bias-2 tool was utilised to assess the risk of bias, and sensitivity analyses were performed to identify publication bias. Certainty analysis (high, moderate, low and/or very low) was conducted using GRADE criteria. RESULTS: Overall, 33 studies met the inclusion criteria and 5 were included in the meta-analysis. Despite a limited pool with several different interventions, we found therapeutic efficacy of xanomeline (M1/M4 agonist) in primary psychotic disorders plus behavioural and psychological symptoms of dementia. Scopolamine showed a significant antidepressant effect in a combined cohort of major depressive and bipolar disorders in the short-term outcome measure, but no effect following cessation of treatment. Results from bias assessments suggest "very low" certainty in the antidepressant effect of scopolamine. Critical limitations of the current literature included low power, high heterogeneity in the patient population and a lack of active comparators. CONCLUSION: While the results are not definitive, findings on muscarinic receptor-targeted interventions in several mental disorders are promising in terms of efficacy and safety, specifically in treating schizophrenia, mood disorders, and behavioural and psychiatric symptoms of Alzheimer's disease. However, orthosteric muscarinic receptor-targeted interventions are associated with a range of peripheral adverse effects that are thought to be mediated via M2/M3 receptors. The orthosteric binding site of muscarinic acetylcholine receptors is remarkably conserved, posing a challenge for subtype-selective interventions; nonetheless allosteric ligands with biased signalling pathways are now in development. We conclude that adequately powered prospective studies with subtype-selective interventions are required to determine the clinical effectiveness of muscarinic-receptor targeted interventions for the treatment of neuropsychiatric disorders.

Examining Sex Differences in Conditioned Place Preference or Aversion to Methamphetamine in Adolescent and Adult Mice.

Adolescence marks a particularly vulnerable period to developing substance use disorders. Human and rodent studies suggest that hypersensitivity to reward may contribute towards such vulnerability when adolescents are exposed to casual drug use. Methamphetamine is a popular illicit substance used by male and female youths. However, age- and sex-specific research in methamphetamine is scarce. The present study therefore aimed to examine potential sex differences in methamphetamine-conditioned place preference in adolescent and adult mice. Mice (n = 16-24/group) were conditioned to methamphetamine (0.1 mg/kg). We observed that regardless of age, females were more hyperactive compared to males. Individually normalized score against baseline preference indicated that on average, adolescents formed stronger preference compared to adults in both sexes. This suggests that adolescents are more sensitive to the rewarding effects of methamphetamine compared to adults. Surprisingly, individual data showed that some mice formed a conditioned place aversion instead of preference, with females less likely to form an aversion compared to males. These results suggest that adolescents may be hypersensitive to methamphetamine's rewarding effects. In addition, female resistance to the aversive effects of methamphetamine may relate to the sex-specific findings in humans, including quicker transition to regular methamphetamine use observed in females compared to males.

Assessing methamphetamine-related cue reactivity in people with methamphetamine use disorder relative to controls.

Methamphetamine use disorder involves methamphetamine-related cues invoking intense craving leading to relapse. Such cue reactivity is thought to arise from Pavlovian conditioning that occurs during the drug-taking experience. Cue reactivity then should be selective to methamphetamine cues (and not other cues), and not observed in people who have never experienced methamphetamine. However, these premises have never been tested and reported using objective measures such as skin conductance response (SCR). The primary aim of this study was to test these premises using a cue reactivity paradigm we developed using control cues. The secondary aim was to explore the relationship between cue reactivity, drug use characteristics, and cognition. Thirty people with a current diagnosis of methamphetamine use disorder and 30 matched controls with no history of substance use disorder were recruited. We observed higher overall subjective reactivity (F = 62.810; p < 0.001) and cue-selective physiological reactivity (F = 5.160; p = 0.026) in people with methamphetamine use disorder but not in controls. Co-morbid sedative use was associated with higher subjective craving (r = 0.521; p = 0.003). People who use methamphetamine intravenously had higher cue-selective SCR than smokers (t = 3.750; p < 0.001). Low inhibitory control measured by the Stroop task was associated with increased craving across the cue paradigm (r = -0.494; p = 0.006). Overall, these results support that cue reactivity in people with methamphetamine use disorder is due to Pavlovian conditioning. Its association with drug use and cognition highlights cue reactivity paradigm's utility in understanding methamphetamine use disorder to develop new treatments targeting cue-induced craving.

Genetics of methamphetamine use disorder: A systematic review and meta-analyses of gene association studies.

Genetic susceptibility to methamphetamine use disorder is poorly understood. No twin or adequately powered genome-wide association studies (GWASs) have been conducted. However, there are a large number of hypothesis-driven candidate gene association studies, which were systematically reviewed herein. Seventy-six studies were identified, investigating markers of 75 different genes. Allele frequencies, odds ratios, 95 % confidence intervals and power were calculated. Risk of bias was also assessed as a quality measure. Meta-analyses were conducted for gene markers if three or more studies were available. Eleven markers from adequately powered studies were significantly associated with methamphetamine use disorder, with Fatty Acid Amide Hydrolase (FAAH) and Brain Derived Neurotrophic Factor (BDNF) representing promising targets. Limitations of these studies include unclear rationale for candidate gene selection, low power and high risk of bias. Future research should include replications to enable more meta-analyses, well-powered GWASs or whole exome or genome sequencing, as well as twin and family studies to further complement the findings of this review to uncover genetic contributions toward methamphetamine use disorder.

Cognition and Related Neural Findings on Methamphetamine Use Disorder: Insights and Treatment Implications From Schizophrenia Research.

Despite the prevalence of methamphetamine (meth) use disorder, research on meth is disproportionately scarce compared to research on other illicit drugs. Existing evidence highlights cognitive deficits as an impediment against daily function and treatment of chronic meth use. Similar deficits are also observed in schizophrenia, and this review therefore draws on schizophrenia research by examining similarities and differences between the two disorders on cognition and related neural findings. While meth use disorder and schizophrenia are two distinct disorders, they are highly co-morbid and share impairments in similar cognitive domains and altered brain structure/function. This narrative review specifically identifies overlapping features such as deficits in learning and memory, social cognition, working memory and inhibitory/impulse control. We report that while working memory deficits are a core feature of schizophrenia, such deficits are inconsistently observed following chronic meth use. Similar structural and functional abnormalities are also observed in cortical and limbic regions between the two disorders, except for cingulate activity where differences are observed. There is growing evidence that targeting cognitive symptoms may improve functional outcome in schizophrenia, with evidence of normalized abnormal brain activity in regions associated with cognition. Considering the overlap between meth use disorder and schizophrenia, targeting cognitive symptoms in people with meth use disorder may also improve treatment outcome and daily function.