Ayahuasca and Dimethyltryptamine Adverse Events and Toxicity Analysis: A Systematic Thematic Review.

The objective of this paper is to conduct a systematic thematic review of adverse events, safety, and toxicity of traditional ayahuasca plant preparations and its main psychoactive alkaloids (dimethyltryptamine [DMT], harmine, harmaline, and tetrahydroharmine), including discussing clinical considerations (within clinical trials or approved settings). A systematic literature search of preclinical, clinical, epidemiological, and pharmacovigilance data (as well as pertinent reviews and case studies) was conducted for articles using the electronic databases of PubMed and Web of Science (to 6 July 2023) and PsycINFO, ClinicalTrials.gov, and Embase (to 21 September 2022) and included articles in English in peer-reviewed journals. Additionally, reference lists were searched. Due to the breadth of the area covered, we presented the relevant data in a thematic format. Our searches revealed 78 relevant articles. Data showed that ayahuasca or DMT is generally safe; however, some adverse human events have been reported. Animal models using higher doses of ayahuasca have shown abortifacient and teratogenic effects. Isolated harmala alkaloid studies have also revealed evidence of potential toxicity at higher doses, which may increase with co-administration with certain medications. Harmaline revealed the most issues in preclinical models. Nevertheless, animal models involving higher-dose synthetic isolates may not necessarily be able to be extrapolated to human use of therapeutic doses of plant-based extracts. Serious adverse effects are rarely reported within healthy populations, indicating an acceptable safety profile for the traditional use of ayahuasca and DMT in controlled settings. Further randomized, controlled trials with judicious blinding, larger samples, and longer duration are needed.

Default Mode Network Modulation by Psychedelics: A Systematic Review.

Psychedelics are a unique class of drug that commonly produce vivid hallucinations as well as profound psychological and mystical experiences. A grouping of interconnected brain regions characterized by increased temporal coherence at rest have been termed the Default Mode Network (DMN). The DMN has been the focus of numerous studies assessing its role in self-referencing, mind wandering, and autobiographical memories. Altered connectivity in the DMN has been associated with a range of neuropsychiatric conditions such as depression, anxiety, post-traumatic stress disorder, attention deficit hyperactive disorder, schizophrenia, and obsessive-compulsive disorder. To date, several studies have investigated how psychedelics modulate this network, but no comprehensive review, to our knowledge, has critically evaluated how major classical psychedelic agents-lysergic acid diethylamide, psilocybin, and ayahuasca-modulate the DMN. Here we present a systematic review of the knowledge base. Across psychedelics there is consistent acute disruption in resting state connectivity within the DMN and increased functional connectivity between canonical resting-state networks. Various models have been proposed to explain the cognitive mechanisms of psychedelics, and in one model DMN modulation is a central axiom. Although the DMN is consistently implicated in psychedelic studies, it is unclear how central the DMN is to the therapeutic potential of classical psychedelic agents. This article aims to provide the field with a comprehensive overview that can propel future research in such a way as to elucidate the neurocognitive mechanisms of psychedelics.

Effect of kava (Piper methysticum) on peripheral gene expression among individuals with generalized anxiety disorder: A post hoc analysis of a randomized controlled trial.

Kava is a South Pacific plant-based medicine with anxiolytic properties, but little is known about the impact kava has on gene expression or whether gene expression can serve as a marker of kava response. This study aimed to determine whether kava treatment alters the expression of genes with physiological relevance to anxiety pathophysiology and whether the baseline expression of these physiologically relevant genes modifies the efficacy of kava treatment. In this post hoc analysis, we examined the expression of 48 genes relevant to the pathophysiology of anxiety collected from a double-blind randomized controlled trial that assessed the efficacy of kava treatment in generalized anxiety disorder. Peripheral blood gene expression was measured in 71 (34 kava, 37 placebo) adults at baseline and in 40 (19 kava, 21 placebo) after 8 weeks of treatment by reverse transcription polymerase chain reaction (PCR). Results revealed that kava decreased the expression of a subunit of the GABAA -rho receptor gene (GABRR2) and catechol-O-methyltransferase (COMT), a gene related to catecholamine metabolism. Kava efficacy was not found to be modified by baseline (pretreatment) expression of relevant genes. Although these results did not withstand statistical correction for multiple comparisons and require external validation, they support the notion that kava's mechanism of action includes interaction with GABAergic and catecholaminergic systems.

Treatment of refractory obsessive-compulsive disorder with nutraceuticals (TRON): a 20-week, open label pilot study.

BACKGROUND: Obsessive-compulsive disorder (OCD) is often challenging to treat and resistant to psychological interventions and prescribed medications. The adjunctive use of nutraceuticals with potential neuromodulatory effects on underpinning pathways such as the glutamatergic and serotonergic systems is one novel approach. OBJECTIVE: To assess the effectiveness and safety of a purpose-formulated combination of nutraceuticals in treating OCD: N-acetyl cysteine, L-theanine, zinc, magnesium, pyridoxal-5' phosphate, and selenium. METHODS: A 20-week open label proof-of-concept study was undertaken involving 28 participants with treatment-resistant DSM-5-diagnosed OCD, during 2017 to 2020. The primary outcome measure was the Yale-Brown Obsessive-Compulsive Scale (YBOCS), administered every 4 weeks. RESULTS: An intention-to-treat analysis revealed an estimated mean reduction across time (baseline to week-20) on the YBOCS total score of -7.13 (95% confidence interval = -9.24, -5.01), with a mean reduction of -1.21 points per post-baseline visit (P ≤ .001). At 20-weeks, 23% of the participants were considered "responders" (YBOCS ≥35% reduction and "very much" or "much improved" on the Clinical Global Impression-Improvement scale). Statistically significant improvements were also revealed on all secondary outcomes (eg, mood, anxiety, and quality of life). Notably, treatment response on OCD outcome scales (eg, YBOCS) was greatest in those with lower baseline symptom levels, while response was limited in those with relatively more severe OCD. CONCLUSIONS: While this pilot study lacks placebo-control, the significant time effect in this treatment-resistant OCD population is encouraging and suggests potential utility especially for those with lower symptom levels. Our findings need to be confirmed or refuted via a follow-up placebo-controlled study.

Effects of Bacopa monnieri (CDRI 08®) in a population of males exhibiting inattention and hyperactivity aged 6 to 14 years: A randomized, double-blind, placebo-controlled trial.

The current study investigated the efficacy of extract of Bacopa monnieri (BM; CDRI 08®) in reducing levels of inattention and hyperactivity in young children. BM has demonstrated improvements in cognitive outcomes in adults, yet little research is available on its effects in younger populations. A 14-week randomized, double-blind, placebo-controlled clinical trial, with placebo run-in and run-out phases, investigated the effects of BM on behavioural, cognitive, mood, and sleep effects in male children aged 6 to 14 years against placebo. One-hundred and twelve participants were recruited into the trial, with 93 datasets available for analysis. No significant behavioural differences were noted between treatment groups. Cognitive outcomes indicated decreased error-making in children taking CDRI 08® (p = .04) and increased speed of reaction time in those taking placebo (p = .04) at study end. Improvements in cognitive flexibility (p = .01), executive functioning (p = .04), interpersonal problems (p = .02), and sleep routine (p = .04) were noted in those consuming CDRI 08® over placebo. CDRI 08® did not improve behavioural outcomes, but may have cognitive, mood and sleep benefits in children aged 6 to 14 years. Further study is required to support the findings presented here.

Yoga for depression and anxiety symptoms in people with cancer: A systematic review and meta-analysis.

OBJECTIVE: Cancer and its treatment can lead to a variety of physical and emotional concerns impacting on those affected, including subclinical or clinical depression and anxiety, which in turn have a significant impact on wellbeing, quality of life and survival. The aim of this review was to evaluate the effect of yoga-based interventions on self-reported depression and anxiety symptoms in people with cancer in randomized controlled trials. METHOD: Six databases were searched to identify relevant studies. Systematic review procedures were followed including a quality assessment. Meta-analysis of suitable studies was conducted. RESULTS: 26 studies from our search criteria were eligible for inclusion for depressive and 16 for anxiety symptoms. Meta-analyses revealed evidence for significant medium effects of yoga on depression symptoms (N = 1,486, g = -0.419, 95% confidence interval [CI] = -0.558 to -0.281, p < 0.001) and anxiety (N = 977, g = -0.347, 95% CI = -0.473 to -0.221, p < 0.001) compared to controls. Subgroup analyses for depressive symptoms revealed significant effects for all analyses performed (type of cancer, type of control, treatment status, duration of intervention or frequency of yoga sessions), with effect sizes being comparable between subgroups. Similar findings were found for anxiety symptoms except for treatment status, where the only significant effect was found when yoga was delivered during active treatment. CONCLUSIONS: This review provides evidence that in people with cancer, yoga-based interventions are associated with amelioration of depression and anxiety symptoms and therefore a promising therapeutic modality for their management. However, the potential for risk of bias together with control group design challenges means the results should be interpreted with caution.

Nutrient and genetic biomarkers of nutraceutical treatment response in mood and psychotic disorders: a systematic review.

Objective: Nutrient and genetic biomarkers in nutraceutical trials may allow for the personalisation of nutraceutical treatment and assist in predicting treatment response. We aimed to synthesise the findings of trials which have included these biomarkers to determine which may be most useful for predicting nutraceutical response in mood and psychotic disorders.Methods: A systematic review was conducted assessing available literature concerning nutraceutical clinical trials in mood and psychotic disorders (major depression, bipolar disorder, schizophrenia) with baseline and endpoint blood nutrient markers or genetic data available.Results: We identified 35 eligible studies (total n = 3836 participants) examining baseline and endpoint nutrient biomarkers and/or genetic polymorphisms. The key result, as reported in 10 out of 11 omega-3 studies, was a strong association between polyunsaturated fatty acid concentrations (mostly EPA and DHA) and psychiatric outcomes, although the exact nature of the association varied between studies and diagnoses. There was no consistent evidence for levels of other nutrients (including Vitamin D, SAM/SAH ratios, carnitine, folate and vitamin B12) relating to treatment response. The evidence for associations between one-carbon cycle genotypes (e.g. MTHFR C677 T, MTR and FOLH1) and treatment response was also inconsistent.Discussion: The available data tentatively supports omega-3 indices as biomarkers of response to omega-3 treatments in mood disorders. Further research with larger samples examining combinations of polymorphisms is required to determine if any genetic factors influence nutraceutical response in mood and psychotic disorders.

A Systematic Review of Nutraceuticals for the Treatment of Bipolar Disorder.

BACKGROUND: Certain nutrient supplements (nutraceuticals) may target neurobiological pathways perturbed in bipolar disorder (BD) such as inflammation, oxidative stress, and mitochondrial dysfunction. Nutraceuticals thus may have a potential role as adjunctive treatments for BD. METHODS: A search of Embase via embase.com, PubMed via PubMed, Cumulated index to nursing and allied health literature (CINAHL) Complete via EBSCO, and Cochrane Central Register of Controlled Clinical Trials via cochranelibrary.com was conducted to identify published randomized controlled trials assessing the efficacy of nutraceuticals on mood symptomatology in adults with BD. Search terms for BD, nutraceuticals, and clinical trials (total search terms = 75) were used to search from inception to February 20, 2020. The Cochrane Collaboration's tool for assessing the risk of bias in randomized trials was used to assess the risk of bias. RESULTS: A total of 1,712 studies were identified through the search. After rigorous screening, 22 studies were included in the review. There was large variability across the studies with 15 different nutraceutical agents assessed and as such insufficient homogeneity for a meta-analysis to be conducted (I2 > 50%). Studies revealed promising, albeit conflicting, evidence for omega-3 fatty acids and N-acetylcysteine. Isolated positive results were reported for coenzyme Q10. CONCLUSION: Given nutraceuticals are tolerable and accessible, they may be useful as potential adjunctive treatments for BD. Nutraceuticals targeting neuroinflammation or mitochondrial activity may have the most potential for the depressive phase. However, further studies are required to determine efficacy.

Plant-based Medicines (Phytoceuticals) in the Treatment of Psychiatric Disorders: A Meta-review of Meta-analyses of Randomized Controlled Trials: Les médicaments à base de plantes (phytoceutiques) dans le traitement des troubles psychiatriques: une méta-revue des méta-analyses d'essais randomisés contrôlés.

OBJECTIVES: Plant-based medicines have had a long-standing history of use in psychiatric disorders. Highly quantified and standardized extracts or isolates may be termed "phytoceuticals," in a similar way that medicinal nutrients are termed as "nutraceuticals." Over the past 2 decades, several meta-analyses have examined the data for a range of plant-based medicines in the treatment of psychiatric disorders. The aim of this international project is to provide a "meta-review" of this top-tier evidence. METHODS: We identified, synthesized, and appraised all available up to date meta-analyses... of randomized controlled trials (RCTs) reporting on the efficacy and effectiveness of individual phytoceuticals across all major psychiatric disorders. RESULTS: Our systematic search identified 9 relevant meta-analyses of RCTs, with primary analyses including outcome data from 5,927 individuals. Supportive meta-analytic evidence was found for St John's wort for major depressive disorder (MDD); curcumin and saffron for MDD or depression symptoms, and ginkgo for total and negative symptoms in schizophrenia. Kava was not effective in treating diagnosed anxiety disorders. We also provide details on 22 traditional Chinese herbal medicine formulas' meta-analyses (primarily for depression studies), all of which revealed highly significant and large effect sizes. Their methodology, reporting, and potential publication bias were, however, of marked concern. The same caveat was noted for the curcumin, ginkgo, and saffron meta-analyses, which may also have significant publication bias. CONCLUSIONS: More rigorous international studies are required to validate the efficacy of these phytoceuticals before treatment recommendations can be made. In conclusion, the breadth of data tentatively supports several phytoceuticals which may be effective for mental disorders alongside pharmaceutical, psychological therapies, and standard lifestyle recommendations.

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.

The Relationship between Oxidative Stress and Anxiety in a Healthy Older Population.

Background/study context: F2-Isoprostanes are putative markers of oxidative stress, one of the processes associated with biological senescence. Evidence exists for elevated F2-Isoprostanes in chronic conditions including psychiatric disorders. Few studies have examined the relationship between oxidative stress and mood in older healthy samples, to establish the influence on mental health. Given current aging demographics in many nations, management of brain and mental health is crucial for longevity, chronic disease management, and quality of life.Method: We investigated the relationship between F2-Isoprostanes, a marker for oxidative stress, and anxiety and mood in 262 healthy adults aged 60-75 years, using baseline data from the Australian Research Council Longevity Intervention (ARCLI; ANZCTR12611000487910), a 12-month nutraceutical intervention study.Results: Higher F2 levels significantly predicted increased Depression-dejection and Anger-hostility subscale scores from the Profile of Mood States (POMS). Fatigue-inertia subscale was predicted by increased Body Mass Index. Spielberger State-Trait Inventory (STAI) scores were significantly higher in females.Conclusion: While the primary outcome data did not find a definitive relationship between F2 and total mood or general anxiety levels, the sub-scale data adds weight toward growing literature that biological processes such as oxidative stress are in part related to mood. This is a modifiable risk factor contributing to physical and mental wellbeing that are crucial to healthy aging.

Multiple lifestyle factors and depressed mood: a cross-sectional and longitudinal analysis of the UK Biobank (N = 84,860).

BACKGROUND: There is now evolving data exploring the relationship between depression and various individual lifestyle factors such as diet, physical activity, sleep, alcohol intake, and tobacco smoking. While this data is compelling, there is a paucity of longitudinal research examining how multiple lifestyle factors relate to depressed mood, and how these relations may differ in individuals with major depressive disorder (MDD) and those without a depressive disorder, as 'healthy controls' (HC). METHODS: To this end, we assessed the relationships between 6 key lifestyle factors (measured via self-report) and depressed mood (measured via a relevant item from the Patient Health Questionnaire) in individuals with a history of or current MDD and healthy controls (HCs). Cross-sectional analyses were performed in the UK Biobank baseline sample, and longitudinal analyses were conducted in those who completed the Mental Health Follow-up. RESULTS: Cross-sectional analysis of 84,860 participants showed that in both MDD and HCs, physical activity, healthy diet, and optimal sleep duration were associated with less frequency of depressed mood (all p < 0.001; ORs 0.62 to 0.94), whereas screen time and also tobacco smoking were associated with higher frequency of depressed mood (both p < 0.0001; ORs 1.09 to 1.36). In the longitudinal analysis, the lifestyle factors which were protective of depressed mood in both MDD and HCs were optimal sleep duration (MDD OR = 1.10; p < 0.001, HC OR = 1.08; p < 0.001) and lower screen time (MDD OR = 0.71; p < 0.001, HC OR = 0.80; p < 0.001). There was also a significant interaction between healthy diet and MDD status (p = 0.024), while a better-quality diet was indicated to be protective of depressed mood in HCs (OR = 0.92; p = 0.045) but was not associated with depressed mood in the MDD sample. In a cross-sectional (OR = 0.91; p < 0.0001) analysis, higher frequency of alcohol consumption was surprisingly associated with reduced frequency of depressed mood in MDD, but not in HCs. CONCLUSIONS: Our data suggest that several lifestyle factors are associated with depressed mood, and in particular, it calls into consideration habits involving increased screen time and a poor sleep and dietary pattern as being partly implicated in the germination or exacerbation of depressed mood.

Cannabis, a cause for anxiety? A critical appraisal of the anxiogenic and anxiolytic properties.

BACKGROUND: Cannabis has been documented for use in alleviating anxiety. However, certain research has also shown that it can produce feelings of anxiety, panic, paranoia and psychosis. In humans, Δ9-tetrahydrocannabinol (THC) has been associated with an anxiogenic response, while anxiolytic activity has been attributed mainly to cannabidiol (CBD). In animal studies, the effects of THC are highly dose-dependent, and biphasic effects of cannabinoids on anxiety-related responses have been extensively documented. A more precise assessment is required of both the anxiolytic and anxiogenic potentials of phytocannabinoids, with an aim towards the development of the 'holy grail' in cannabis research, a medicinally-active formulation which may assist in the treatment of anxiety or mood disorders without eliciting any anxiogenic effects. OBJECTIVES: To systematically review studies assessing cannabinoid interventions (e.g. THC or CBD or whole cannabis interventions) both in animals and humans, as well as recent epidemiological studies reporting on anxiolytic or anxiogenic effects from cannabis consumption. METHOD: The articles selected for this review were identified up to January 2020 through searches in the electronic databases OVID MEDLINE, Cochrane Central Register of Controlled Trials, PubMed, and PsycINFO. RESULTS: Acute doses of CBD were found to reduce anxiety both in animals and humans, without having an anxiogenic effect at higher doses. Epidemiological studies tend to support an anxiolytic effect from the consumption of either  CBD or THC, as well as whole plant cannabis. Conversely, the available human clinical studies demonstrate a common anxiogenic response to THC (especially at higher doses). CONCLUSION: Based on current data, cannabinoid therapies (containing primarily CBD) may provide a more suitable treatment for people with pre-existing anxiety or as a potential adjunctive role in managing anxiety or stress-related disorders. However, further research is needed to explore other cannabinoids and phytochemical constituents present in cannabis (e.g. terpenes) as anxiolytic interventions. Future clinical trials involving patients with anxiety disorders are warranted due to the small number of available human studies.

Handgrip Strength Is Associated With Hippocampal Volume and White Matter Hyperintensities in Major Depression and Healthy Controls: A UK Biobank Study.

OBJECTIVE: Emerging evidence suggests that handgrip strength (a proxy for muscular fitness) is associated with better cognitive performance in people with major depressive disorder (MDD). The underlying processes are unclear, although hippocampal volume (HCV) reductions and white matter hyperintensities (WMHs) have been implicated. Therefore, we investigated the associations between handgrip strength and various brain region volumes and WMHs in MDD and healthy controls (HCs). METHODS: This study is a cross-sectional analysis of handgrip strength and neuroimaging data from the UK Biobank. Generalized linear models were used to assess the relationship between grip strength and gray matter, white matter, total brain volume, left and right hippocampus volume, and WMHs in MDD and HCs, adjusting for age, sex, education, and body weight. RESULTS: The sample included 527 people with MDD (54.3 ± 7.3 years, 37.2% male) and 1764 HCs (56.6 ± 7.2 years, 53% male). In MDD, stronger handgrip was significantly associated with increased left (coefficient ± SE = 108.1 ± 27.6, t = 3.92) and right (76.8 ± 30.4, t = 2.53) HCV. In HCs, only right HCV related to handgrip strength (44.8 ± 18.1, t = 2.47). Interaction analyses found stronger associations between grip strength and HCV in MDD compared with HCs, for both hippocampal regions. Stronger handgrip was associated with reduced WMHs in people with MDD (-0.24 ± 0.07, t = -3.24) and HCs (-0.11 ± 0.04, t = -2.47). Maximal handgrip strength was not associated with gray matter, white matter, or total brain volumes in either group. CONCLUSIONS: Stronger grip strength is associated with greater left and right HCV and reduced WMHs in MDD. Future research should investigate directionality and consider if interventions targeting strength/muscular fitness can improve brain health and reduce the neurocognitive abnormalities associated with MDD.

EPA and DHA as markers of nutraceutical treatment response in major depressive disorder.

PURPOSE: Depression clinical trials are increasingly studying biomarkers to predict and monitor response to treatment. Assessment of biomarkers may reveal subsets of patients who are responsive to nutraceutical treatment, which may facilitate a personalized approach to treating depression. METHODS: This is a post hoc analysis of an 8-week, double-blind, randomized, controlled trial (n = 158) investigating a combination nutraceutical comprising Omega-3 (EPA 1 g/DHA 656 mg), SAMe, zinc, 5-HTP, folinic acid, and co-factors versus placebo for the treatment of Major Depressive Disorder. The study explored levels of polyunsaturated fatty acids, folate, vitamin B12, zinc, homocysteine, and BDNF as possible predictors and correlates of response to nutraceutical supplementation. RESULTS: Concentrations of EPA and DHA in red cell membranes increased in response to treatment and were significantly correlated with a decrease in depressive symptoms during active treatment (p = 0.003 and p = 0.029; respectively). Higher baseline levels of omega-6 fatty acid also correlated with depression reduction in the active treatment group ( p = 0.011). No other biomarkers were associated with a lessening of depressive symptoms. CONCLUSION: Changes in fatty acid levels resulting from a nutraceutical combination containing EPA and DHA provide a response biomarker in treating depression.

Improvement of cognitive function in schizophrenia with N-acetylcysteine: A theoretical review.

Objectives: Schizophrenia is a debilitating psychiatric illness associated with positive and negative symptoms as well as significant impairments in cognition. Current antipsychotic medications do not alleviate these cognitive deficits, and more effective therapeutic options are required. Increased oxidative stress and altered antioxidant levels, including glutathione (GSH) have been observed both in individuals with cognitive impairment and in people with schizophrenia. A GSH precursor, the antioxidant N-acetylcysteine (NAC) has been investigated as a novel treatment for the cognitive symptoms of schizophrenia, and recent research suggests that NAC may be a promising adjunctive treatment option. However, the current literature lacks integration as to why NAC may effectively improve cognition in schizophrenia. The present theoretical synthesis aimed to address this gap by examining the processes by which NAC may improve cognitive function in schizophrenia. Methods: The schizophrenia literature was reviewed in three key domains: cognitive impairment, the relationship between oxidative stress and cognition, and the efficacy of NAC as a novel treatment. This led to a theoretical analysis of the neurobiological processes by which NAC may improve cognition in schizophrenia. Results: This theoretical review concluded that improved cognition may result from a combination of factors, including decreased oxidative stress, neuroprotection of cognitive networks and an increase in glutamatergic modulation of the N-methyl-d-aspartate receptor system. Whilst a number of mechanisms by which NAC may improve cognition and symptoms in schizophrenia have been proposed, there is still limited understanding of the specific metabolic pathways involved and how they interrelate and modify specific symptomology. Discussion: Exploration of how NAC treatment may act to improve cognitive function could guide clinical trials by investigation of the specific neurotransmitter systems and processes involved, allowing for targeted neurological outcome measures. Future research would benefit from the investigation of both in vivo cortical GSH concentration and peripheral plasma GSH in a population of individuals with chronic schizophrenia.

Medicinal cannabis for psychiatric disorders: a clinically-focused systematic review.

BACKGROUND: Medicinal cannabis has received increased research attention over recent years due to loosening global regulatory changes. Medicinal cannabis has been reported to have potential efficacy in reducing pain, muscle spasticity, chemotherapy-induced nausea and vomiting, and intractable childhood epilepsy. Yet its potential application in the field of psychiatry is lesser known. METHODS: The first clinically-focused systematic review on the emerging medical application of cannabis across all major psychiatric disorders was conducted. Current evidence regarding whole plant formulations and plant-derived cannabinoid isolates in mood, anxiety, sleep, psychotic disorders and attention deficit/hyperactivity disorder (ADHD) is discussed; while also detailing clinical prescription considerations (including pharmacogenomics), occupational and public health elements, and future research recommendations. The systematic review of the literature was conducted during 2019, assessing the data from all case studies and clinical trials involving medicinal cannabis or plant-derived isolates for all major psychiatric disorders (neurological conditions and pain were omitted). RESULTS: The present evidence in the emerging field of cannabinoid therapeutics in psychiatry is nascent, and thereby it is currently premature to recommend cannabinoid-based interventions. Isolated positive studies have, however, revealed tentative support for cannabinoids (namely cannabidiol; CBD) for reducing social anxiety; with mixed (mainly positive) evidence for adjunctive use in schizophrenia. Case studies suggest that medicinal cannabis may be beneficial for improving sleep and post-traumatic stress disorder, however evidence is currently weak. Preliminary research findings indicate no benefit for depression from high delta-9 tetrahydrocannabinol (THC) therapeutics, or for CBD in mania. One isolated study indicates some potential efficacy for an oral cannabinoid/terpene combination in ADHD. Clinical prescriptive consideration involves caution in the use of high-THC formulations (avoidance in youth, and in people with anxiety or psychotic disorders), gradual titration, regular assessment, and caution in cardiovascular and respiratory disorders, pregnancy and breast-feeding. CONCLUSIONS: There is currently encouraging, albeit embryonic, evidence for medicinal cannabis in the treatment of a range of psychiatric disorders. Supportive findings are emerging for some key isolates, however, clinicians need to be mindful of a range of prescriptive and occupational safety considerations, especially if initiating higher dose THC formulas.

Physical Activity as a Predictor of Clinical Trial Outcomes in Bipolar Depression: A Subanalysis of a Mitochondrial-Enhancing Nutraceutical Randomized Controlled Trial.

OBJECTIVES: Individuals with bipolar disorder (BD) generally engage in low levels of physical activity (PA), and yet few studies have investigated the relationship between PA and change in BD symptom severity. The aim of this subanalysis of an adjunctive nutraceutical randomized controlled trial for the treatment of bipolar depression was to explore the relationship between PA, the active adjunctive treatments (a nutraceutical "mitochondrial cocktail"), and clinical outcomes. METHODS: Participants with bipolar depression were randomized to receive N-acetylcysteine alone, N-acetylcysteine with a combination of nutraceuticals (chosen for the potential to increase mitochondrial activity), or placebo for 16 weeks. Participants (n = 145) who completed the International Physical Activity Questionnaire-Short Form (IPAQ-SF; measured at Week 4) were included in this exploratory subanalysis. Assessments of BD symptoms, functioning, and quality of life were completed at monthly visits up until Week 20. Generalised Estimating Equations were used to explore whether IPAQ-SF scores were a moderator of treatment received on outcomes of the study. RESULTS: Week-4 PA was not related to changes in Montgomery Åsberg Depression Rating Scale scores across the study until Week 20. However, participants who engaged in more PA and who received the combination treatment were more likely to have a reduction in scores on the Bipolar Depression Rating Scale (P = 0.03). However, this was not consistent in all domains explored using the IPAQ-SF. Participants who engaged in higher levels of PA also experienced greater improvement in social and occupational functioning and less impairment in functioning due to their psychopathology and improvement in quality of life at Week 20, irrespective of treatment. CONCLUSIONS: This study provides novel evidence of the association between PA and reduction in BD symptoms in a nutraceutical clinical trial. However, further research assessing the potential synergistic effects of PA in BD is required.

Kava for generalised anxiety disorder: A 16-week double-blind, randomised, placebo-controlled study.

OBJECTIVE: Previous randomised, double-blind, placebo-controlled studies have shown that Kava (a South Pacific medicinal plant) reduced anxiety during short-term administration. The objective of this randomised, double-blind, placebo-controlled study was to perform a larger, longer-term trial assessing the efficacy and safety of Kava in the treatment of generalised anxiety disorder and to determine whether gamma-aminobutyric acid transporter (SLC6A1) single-nucleotide polymorphisms were moderators of response. METHODS: The trial was a phase III, multi-site, two-arm, 16-week, randomised, double-blind, placebo-controlled study investigating an aqueous extract of dried Kava root administered twice per day in tablet form (standardised to 120 mg of kavalactones twice/day) in 171 currently non-medicated anxious participants with diagnosed generalised anxiety disorder. The trial took place in Australia. RESULTS: An analysis of 171 participants revealed a non-significant difference in anxiety reduction between the Kava and placebo groups (a relative reduction favouring placebo of 1.37 points; p = 0.25). At the conclusion of the controlled phase, 17.4% of the Kava group were classified as remitted (Hamilton Anxiety Rating Scale score < 7) compared to 23.8% of the placebo group (p = 0.46). No SLC6A1 polymorphisms were associated with treatment response, while carriers of the rs2601126 T allele preferentially respond to placebo (p = 0.006). Kava was well tolerated aside from poorer memory (Kava = 36 vs placebo = 23; p = 0.044) and tremor/shakiness (Kava = 36 vs placebo = 23; p = 0.024) occurring more frequently in the Kava group. Liver function test abnormalities were significantly more frequent in the Kava group, although no participant met criteria for herb-induced hepatic injury. CONCLUSION: While research has generally supported Kava in non-clinical populations (potentially for more 'situational' anxiety as a short-term anxiolytic), this particular extract was not effective for diagnosed generalised anxiety disorder.

Diet quality, dietary inflammatory index and body mass index as predictors of response to adjunctive N-acetylcysteine and mitochondrial agents in adults with bipolar disorder: A sub-study of a randomised placebo-controlled trial.

AIMS: We aimed to explore the relationships between diet quality, dietary inflammatory potential or body mass index and outcomes of a clinical trial of nutraceutical treatment for bipolar depression. METHODS: This is a sub-study of a randomised controlled trial of participants with bipolar depression who provided dietary intake data (n = 133). Participants received 16 weeks adjunctive treatment of either placebo or N-acetylcysteine-alone or a combination of mitochondrial-enhancing nutraceuticals including N-acetylcysteine (combination treatment). Participants were followed up 4 weeks post-treatment discontinuation (Week 20). Diet was assessed by the Cancer Council Victoria Dietary Questionnaire for Epidemiological Studies, Version 2, converted into an Australian Recommended Food Score to measure diet quality, and energy-adjusted dietary inflammatory index score to measure inflammatory potential of diet. Body mass index was also measured. Generalised estimating equation models were used to assess whether diet quality, energy-adjusted dietary inflammatory index score and/or body mass index were predictors of response to significant outcomes of the primary trial: depression symptoms, clinician-rated improvement and functioning measures. RESULTS: In participants taking combination treatment compared to placebo, change in depression scores was not predicted by Australian Recommended Food Score, dietary inflammatory index or body mass index scores. However, participants with better diet quality (Australian Recommended Food Score) reported reduced general depression and bipolar depression symptoms (p = 0.01 and p = 0.03, respectively) and greater clinician-rated improvement (p = 0.02) irrespective of treatment and time. Participants who had a more anti-inflammatory dietary inflammatory index had less impairment in functioning (p = 0.01). Combination treatment may attenuate the adverse effects of pro-inflammatory diet (p = 0.03) on functioning. Participants with lower body mass index who received combination treatment (p = 0.02) or N-acetylcysteine (p = 0.02) showed greater clinician-rated improvement. CONCLUSION: These data support a possible association between diet (quality and inflammatory potential), body mass index and response to treatment for bipolar depression in the context of a nutraceutical trial. The results should be interpreted cautiously because of limitations, including numerous null findings, modest sample size and being secondary analyses.