Predictors of the placebo response in a nutraceutical randomized controlled trial for depression.

OBJECTIVE: The placebo response in depression studies is the change in symptoms amongst those who receive an inactive treatment. Many well-designed randomized controlled trials (RCTs) of depression have a high proportion of placebo responders, with little understanding as to why. The present study assesses characteristics associated with the placebo response in a nutraceutical trial with a large proportion of placebo responders. METHODS: This is a secondary analysis of a nutraceutical depression RCT which identified no overall treatment benefit relative to placebo (n = 69 in placebo group). We investigated participant characteristics such as socio-demographics, clinical features, and recruitment methods, and their association with the placebo response. Monoaminergic genetic polymorphisms were also assessed. Placebo response was measured based on change in Montgomery-Asberg Depression Rating Scale score. The association of these hypothesis-driven variables of interest and the placebo response was examined using linear mixed effects models. RESULTS: Greater levels of education, particularly pursuing post-high school education, better self-reported general health, marriage/de facto, greater improvement in the first trial week, and more failed antidepressant therapies in the current depressive episode were associated with greater placebo response. An increased placebo response was not found in those recruited via social media nor in those with concomitant antidepressant therapy. Single nucleotide polymorphisms from the tryptophan hydroxylase 1 (TPH1) gene (A779C and A218C) were weakly associated with greater placebo response, although the evidence was attenuated after accounting for multiple comparisons. CONCLUSION: This is, to our knowledge, the first study within nutraceutical research for depression to assess the association between participant characteristics and variation in the placebo response. Several variables appeared to predict the placebo response. Such findings may encourage future trial designs which could dampen placebo response, improve assay sensitivity, and allow for treatment effects to be potentially more detectable. Please cite this article as: Arnold R, Murphy-Smith J, Ng CH, Mischoulon D, Byrne GJ, Bousman CA, Stough C, Berk M, Sarris J. Predictors of the placebo response in a nutraceutical randomized controlled trial for depression. J Integr Med. 2024; 22(1): 46-53.

Neuroimaging Insights: Kava's (Piper methysticum) Effect on Dorsal Anterior Cingulate Cortex GABA in Generalized Anxiety Disorder.

Generalised Anxiety Disorder (GAD) is a prevalent, chronic mental health disorder. The measurement of regional brain gamma-aminobutyric acid (GABA) offers insight into its role in anxiety and is a potential biomarker for treatment response. Research literature suggests Piper methysticum (Kava) is efficacious as an anxiety treatment, but no study has assessed its effects on central GABA levels. This study investigated dorsal anterior cingulate (dACC) GABA levels in 37 adult participants with GAD. GABA was measured using proton magnetic resonance spectroscopy (1H-MRS) at baseline and following an eight-week administration of Kava (standardised to 120 mg kavalactones twice daily) (n = 20) or placebo (n = 17). This study was part of the Kava for the Treatment of GAD (KGAD; ClinicalTrials.gov: NCT02219880), a 16-week intervention study. Compared with the placebo group, the Kava group had a significant reduction in dACC GABA (p = 0.049) at eight weeks. Baseline anxiety scores on the HAM-A were positively correlated with GABA levels but were not significantly related to treatment. Central GABA reductions following Kava treatment may signal an inhibitory effect, which, if considered efficacious, suggests that GABA levels are modulated by Kava, independent of reported anxiety symptoms. dACC GABA patterns suggest a functional role of higher levels in clinical anxiety but warrants further research for symptom benefit. Findings suggest that dACC GABA levels previously un-examined in GAD could serve as a biomarker for diagnosis and treatment response.

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.

Cancer survivors' experiences, barriers and preferences with yoga: A cross-sectional survey to inform a yoga intervention.

PURPOSE: Evidence suggests that yoga may help improve cancer-related symptoms though knowledge of the experiences, barriers and preferences of people diagnosed with cancer is limited. This study sought to examine the use of yoga in an Australian sample and identify the experiences and preferences associated with undertaking yoga practice as formative research to help inform a future yoga intervention. METHODS: Adults diagnosed with any type of cancer completed a cross-sectional survey including questions regarding their demographics, experiences and preferences for yoga practice. RESULTS: Sixty-eight people who had been diagnosed with cancer completed the survey. Most of the participants (70.8%) had practiced yoga since their diagnosis. A variety of reasons for practice were endorsed, and benefits experienced included physical and psychological factors. The most common barrier to practice was related to the physical ability to undertake yoga. Participants indicated a preference for group classes (44.1%), with a frequency of practice of 2-3 times per week (60.3%), 60 min in length (75%). The preferred time of practice was 9am-12pm (51.5%) and travel distance 5-10 km (44.1%). Online yoga delivery was endorsed, with participants preferring pre-recorded sessions. CONCLUSIONS: Results from this study provide insights into the experiences, barriers and preferences for yoga practice in people with cancer which will assist in developing yoga programs in this cohort to investigate the effects on cancer and treatment-related symptoms.

A literature review of the studies concerning selected plant-derived adaptogens and their general function in body with a focus on animal studies.

BACKGROUND: Adaptogens are generally referred to the substances, mostly found in plants, which non-specifically increase resilience and chances of survival by activation of signaling pathways in affected cells. PURPOSE: This literature review was conducted to summarize the investigation, until March 2021, on selected adaptogenic plants and plant-derived substances. STUDY DESIGN: Electronic databases were searched (up to March 2021) for in vitro and animal studies, as well as clinical trials. Moreover, all modes of action connected with the adaptogenic effects of plants and phytochemicals were collected. METHODS: The search of relevant studies was performed within electronic databases including Scopus, Science Direct, PubMed, and Cochrane library. The most important keywords were adaptogen, plant, phytochemical, and plant-derived. RESULTS: The most investigated medicinal herbs for their adaptogenic activity are Eleutherococcus senticosus, Panax ginseng, Withania somnifera, Schisandra chinensis, and Rhodiola spp., salidroside, ginsenosides, andrographolide, methyl jasmonate, cucurbitacin R, dichotosin, and dichotosininare are phytochemicals that have shown a considerable adaptogenic activity. Phytochemicals that have been demonstrated adaptogenic properties mainly belong to flavonoids, terpenoids, and phenylpropanoid glycosides. CONCLUSION: It is concluded that the main modes of action of the selected adaptogenic plants are stress modulatory, antioxidant, anti-fatigue, and physical endurance enhancement. Other properties were nootropic, immunomodulatory, cardiovascular, and radioprotective activities.

Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce.

OBJECTIVES: The therapeutic use of nutrient-based 'nutraceuticals' and plant-based 'phytoceuticals' for the treatment of mental disorders is common; however, despite recent research progress, there have not been any updated global clinical guidelines since 2015. To address this, the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Disorders (CANMAT) convened an international taskforce involving 31 leading academics and clinicians from 15 countries, between 2019 and 2021. These guidelines are aimed at providing a definitive evidence-informed approach to assist clinicians in making decisions around the use of such agents for major psychiatric disorders. We also provide detail on safety and tolerability, and clinical advice regarding prescription (e.g. indications, dosage), in addition to consideration for use in specialised populations. METHODS: The methodology was based on the WFSBP guidelines development process. Evidence was assessed based on the WFSBP grading of evidence (and was modified to focus on Grade A level evidence - meta-analysis or two or more RCTs - due to the breadth of data available across all nutraceuticals and phytoceuticals across major psychiatric disorders). The taskforce assessed both the 'level of evidence' (LoE) (i.e. meta-analyses or RCTs) and the assessment of the direction of the evidence, to determine whether the intervention was 'Recommended' (+++), 'Provisionally Recommended' (++), 'Weakly Recommended' (+), 'Not Currently Recommended' (+/-), or 'Not Recommended' (-) for a particular condition. Due to the number of clinical trials now available in the field, we firstly examined the data from our two meta-reviews of meta-analyses (nutraceuticals conducted in 2019, and phytoceuticals in 2020). We then performed a search of additional relevant RCTs and reported on both these data as the primary drivers supporting our clinical recommendations. Lower levels of evidence, including isolated RCTs, open label studies, case studies, preclinical research, and interventions with only traditional or anecdotal use, were not assessed. RESULTS: Amongst nutraceuticals with Grade A evidence, positive directionality and varying levels of support (recommended, provisionally recommended, or weakly recommended) was found for adjunctive omega-3 fatty acids (+++), vitamin D (+), adjunctive probiotics (++), adjunctive zinc (++), methylfolate (+), and adjunctive s-adenosyl methionine (SAMe) (+) in the treatment of unipolar depression. Monotherapy omega-3 (+/-), folic acid (-), vitamin C (-), tryptophan (+/-), creatine (+/-), inositol (-), magnesium (-), and n-acetyl cysteine (NAC) (+/-) and SAMe (+/-) were not supported for this use. In bipolar disorder, omega-3 had weak support for bipolar depression (+), while NAC was not currently recommended (+/-). NAC was weakly recommended (+) in the treatment of OCD-related disorders; however, no other nutraceutical had sufficient evidence in any anxiety-related disorder. Vitamin D (+), NAC (++), methylfolate (++) were recommended to varying degrees in the treatment of the negative symptoms in schizophrenia, while omega-3 fatty acids were not, although evidence suggests a role for prevention of transition to psychosis in high-risk youth, with potential pre-existing fatty acid deficiency. Micronutrients (+) and vitamin D (+) were weakly supported in the treatment of ADHD, while omega-3 (+/-) and omega-9 fatty acids (-), acetyl L carnitine (-), and zinc (+/-) were not supported. Phytoceuticals with supporting Grade A evidence and positive directionality included St John's wort (+++), saffron (++), curcumin (++), and lavender (+) in the treatment of unipolar depression, while rhodiola use was not supported for use in mood disorders. Ashwagandha (++), galphimia (+), and lavender (++) were modestly supported in the treatment of anxiety disorders, while kava (-) and chamomile (+/-) were not recommended for generalised anxiety disorder. Ginkgo was weakly supported in the adjunctive treatment of negative symptoms of schizophrenia (+), but not supported in the treatment of ADHD (+/-). With respect to safety and tolerability, all interventions were deemed to have varying acceptable levels of safety and tolerability for low-risk over-the-counter use in most circumstances. Quality and standardisation of phytoceuticals was also raised by the taskforce as a key limiting issue for firmer confidence in these agents. Finally, the taskforce noted that such use of nutraceuticals or phytoceuticals be primarily recommended (where supportive evidence exists) adjunctively within a standard medical/health professional care model, especially in cases of more severe mental illness. Some meta-analyses reviewed contained data from heterogenous studies involving poor methodology. Isolated RCTs and other data such as open label or case series were not included, and it is recognised that an absence of data does not imply lack of efficacy. CONCLUSIONS: Based on the current data and clinician input, a range of nutraceuticals and phytoceuticals were given either a supportive recommendation or a provisional recommendation across a range of various psychiatric disorders. However several had only a weak endorsement for potential use; for a few it was not possible to reach a clear recommendation direction, largely due to mixed study findings; while some other agents showed no obvious therapeutic benefit and were clearly not recommended for use. It is the intention of these guidelines to inform psychiatric/medical, and health professional practice globally.

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.

Adverse effects of ayahuasca: Results from the Global Ayahuasca Survey.

INTRODUCTION: Ayahuasca is a plant-based decoction native to Amazonia, where it has a long history of use in traditional medicine. Contemporary ritual use of ayahuasca has been expanding throughout the world for mental health purposes, and for spiritual and personal growth. Although researchers have been conducting clinical trials and observational studies reporting medical and psychological benefits, most of these do not report ayahuasca's immediate or medium-term adverse effects, so these are underrepresented in the literature. With the expansion of ayahuasca ceremonies from their traditional contexts to countries around the world, there is an important public health question regarding the risk/benefit balance of its use. METHODS: We used data from an online Global Ayahuasca Survey (n = 10,836) collected between 2017 and 2019 involving participants from more than 50 countries. Principal component analysis was performed to assess group effects. Logistic regression analysis was performed to test for adverse effects associated with history of ayahuasca use, clinical, context of use and spiritual effect variables. RESULTS: Acute physical health adverse effects (primarily vomiting) were reported by 69.9% of the sample, with 2.3% reporting the need for subsequent medical attention. Adverse mental health effects in the weeks or months following consumption were reported by 55.9% of the sample, however, around 88% considered such mental health effects as part of a positive process of growth or integration. Around 12% sought professional support for these effects. Physical adverse effects were related to older age at initial use of ayahuasca, having a physical health condition, higher lifetime and last year ayahuasca use, having a previous substance use disorder diagnosis, and taking ayahuasca in a non-supervised context. Mental health adverse effects were positively associated with anxiety disorders; physical health conditions; and the strength of the acute spiritual experience; and negatively associated with consumption in religious settings. CONCLUSIONS: While there is a high rate of adverse physical effects and challenging psychological effects from using ayahuasca, they are not generally severe, and most ayahuasca ceremony attendees continue to attend ceremonies, suggesting they perceive the benefits as outweighing any adverse effects. Knowing what variables might predict eventual adverse effects may serve in screening of, or providing additional support for, vulnerable subjects. Improved understanding of the ayahuasca risk/benefit balance can also assist policy makers in decisions regarding potential regulation and public health responses.

Psychotherapeutic and neurobiological processes associated with ayahuasca: A proposed model and implications for therapeutic use.

Ayahuasca is a psychoactive Amazonian plant brew. It is usually made from the Banisteriopsis caapi vine (Spruce ex Griseb. Morton, Malpighiaceae), which contains three primary harmala alkaloids, along with the leaves of Psychotria viridis (Ruiz et Pavon, Rubiaceae) in which the potent psychedelic dimethyltryptamine (DMT) is found. DMT-harmaloid concoctions have gained popularity in recent years, due to growing anecdotal and scientific reports of therapeutic benefits associated with their consumption. Ayahuasca is now ingested in a variety of different settings across the globe, from traditional ethnobotanical to so called "neo-shamanic" ceremonies. Furthermore, related preparations involving alternative sources of DMT and harmala alkaloids are becoming increasingly common as knowledge of ayahuasca continues to spread internationally. This article reviews the existing literature and draws on original qualitative data from a large cross-sectional study of ayahuasca drinkers, to propose a model of psychotherapeutic processes associated with the consumption of ayahuasca. We assert that it is these processes, facilitated by a range of neurobiological effects, that lead to beneficial mental health and wellbeing outcomes. Our proposed model identifies five key psychotherapeutic processes or effects inherent to the ayahuasca experience; somatic effects; introspection and emotional processing; increased Self-connection; increased spiritual connection, and finally the gaining of insights and new perspectives. We note some important differences in these processes compared with other classic psychedelics as well as the implications of the model for the therapeutic use of ayahuasca. Improved understanding of the psychotherapeutic processes involved with the ayahuasca experience will better equip practitioners to work with this potentially transformative concoction and enable the optimization of therapeutic treatment models for potential clinical use.

Zao Ren An Shen capsule for insomnia: a double-blind, randomized, placebo-controlled trial.

STUDY OBJECTIVES: The aim of this study was to test the efficacy and safety of Zao Ren An Shen (ZRAS) capsule, a Chinese herbal medicine product, for the treatment of insomnia. METHODS: We conducted a double-blind randomized placebo-controlled trial. After a one-week placebo run-in, a total of 85 people with insomnia were randomly allocated to receive ZRAS or placebo for 4 weeks. The primary outcomes were insomnia severity assessed with the Insomnia Severity Index (ISI) and the number of participants with adverse events (AEs). Secondary outcomes included objective and subjective sleep parameters, psychological status, fatigue level, quality of life, acceptability, and tolerability. RESULTS: A nonsignificant (p > .05) difference of 0.7 points in ISI in favor of ZRAS capsule was found at the end of the treatment. The number of participants with AEs was not significantly different (p > .05) between the two groups. Except for subjective sleep onset latency, which had a nonsignificant (p > .05) medium effect (Cohen's d = 0.5), the effects in secondary efficacy outcomes were all small (Cohen's d < .4) and nonsignificant (p > .05). The acceptability and tolerability were high in the active group. CONCLUSIONS: ZRAS capsule is safe, acceptable, and tolerable, yet not more effective than placebo in the treatment of insomnia. As previous evidence showed that Chinese herbal medicine was effective for insomnia, these results may be explained by the dose of the product, which was lower than the dose generally used in the clinic.Registration: This clinical trial was registered in Australia New Zealand Clinical Trial Registry (registration number ACTRN12619000140156) under the name "Impact of Zao Ren An Shen (ZRAS) capsule on chronic insomnia patients' insomnia severity: A randomized-controlled trial" (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376730&isReview=true).

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 a group-based lifestyle medicine for depression: A pilot randomized controlled trial.

Given the growing evidence that a range of lifestyle factors are involved in the etiology of depression, a 'lifestyle medicine' approach can be potentially safe and cost-effective to prevent or treat depression. To examine the effects and acceptability of a group-based, integrative lifestyle medicine intervention as a standalone treatment for managing depressive symptoms, a pilot randomized controlled trial (RCT) was conducted in a Chinese adult population in 2018. Participants (n = 31) with PHQ-9 score above the cut-off of ≥ 10, which was indicative of moderate to severe depression, were recruited from the general community in Hong Kong and randomly assigned to lifestyle medicine group (LM group) or care-as-usual group (CAU group) in a ratio of 1:1. Participants in the LM group received 2-hour group sessions once per week for six consecutive weeks, which covered diet, exercise, mindfulness, psychoeducation, and sleep management. Linear mixed-effects model analyses showed that the LM group had a significant reduction in PHQ-9 scores compared to the CAU group at immediate posttreatment and 12-week posttreatment follow-up (d = 0.69 and 0.73, respectively). Moreover, there were significantly greater improvements in anxiety, stress, and insomnia symptoms (measured by DASS-21 and ISI) at all time points in the LM group (d = 0.42-1.16). The results suggests that our 6-week group-based, integrative lifestyle intervention program is effective in lowering depressive, anxiety, stress, and insomnia symptoms in the Chinese population. Further studies in clinical populations with a larger sample size and longer follow-up are warranted.

Effects of cannabis ingestion on endometriosis-associated pelvic pain and related symptoms.

BACKGROUND: The use of cannabis for symptoms of endometriosis was investigated utilising retrospective archival data from Strainprint Technologies Ltd., a Canadian data technology company with a mobile phone application that tracks a range of data including dose, mode of administration, chemovar and their effects on various self-reported outcomes, including pelvic pain. METHODS: A retrospective, electronic record-based cohort study of StrainprintTM users with self-reported endometriosis was conducted. Self-rated cannabis efficacy, defined as a function of initial and final symptom ratings, was investigated across the included symptom clusters of cramps, pelvic pain, gastrointestinal pain, nausea, depression, and low libido. Cannabis dosage form, dose and cannabinoid ratio information was also recorded. RESULTS: A total number of 252 participants identifying as suffering endometriosis recorded 16193 sessions using cannabis between April 2017 and February 2020. The most common method of ingestion was inhalation (n = 10914, 67.4%), with pain as the most common reported symptom being treated by cannabis (n = 9281, 57.3%). Gastrointestinal symptoms, though a less common reason for cannabis usage (15.2%), had the greatest self-reported improvement after use. Inhaled forms had higher efficacy for pain, while oral forms were superior for mood and gastrointestinal symptoms. Dosage varied across ingestion methods, with a median dose of 9 inhalations (IQR 5 to 11) for inhaled dosage forms and 1 mg/mL (IQR 0.5 to 2) for other ingested dosage forms. The ratio of THC to CBD had a statistically significant, yet clinically small, differential effect on efficacy, depending on method of ingestion. CONCLUSIONS: Cannabis appears to be effective for pelvic pain, gastrointestinal issues and mood, with effectiveness differing based on method of ingestion. The greater propensity for use of an inhaled dosage delivery may be due to the rapid onset of pain-relieving effects versus the slower onset of oral products. Oral forms appeared to be superior compared to inhaled forms in the less commonly reported mood or gastrointestinal categories. Clinical trials investigating the tolerability and effectiveness of cannabis for endometriosis pain and associated symptoms are urgently required.

Potential mental and physical benefits of supplementation with a high-dose, B-complex multivitamin/mineral supplement: What is the evidence?

INTRODUCTION: Objective: to perform a systematic literature review to examine the effects of high-dose, B-complex multivitamin/mineral supplementation on physical, mental, and energy outcomes in healthy and 'at-risk' (suboptimal nutritional status/subclinical symptoms at baseline) adult populations. Methods: PubMed was searched for relevant randomized controlled trials until January 2020. Results: overall, 136 publications were identified. In the seven randomised, double-blind, placebo-controlled studies considered eligible for inclusion, supplementation in healthy populations predominantly showed improvements in perceived stress, physical stamina, concentration, and general mental health, and significant reductions in anxiety and improvements in self-reported vigour. However, not all of these outcomes were significant, and statistical correction for multiple outcomes was not commonly employed. Studies investigating brain mapping following supplementation indicated increased functional activity in brain regions related to processing of attention, executive control, and working memory during cognitive tasks. Conclusions: while there is certainly a need for further studies on the neurocognitive and physical benefits of micronutrient supplementation, this review provides generally supportive evidence for the benefits of a high-dose, B-complex multivitamin/mineral supplement in healthy and at-risk populations in terms of physical, mental, and energy outcomes.

INTRODUCCIÓN: Objetivo: realizar una revisión sistemática de la literatura para valorar los efectos de la administración de suplementos multivitamínicos/minerales del complejo B en dosis altas sobre los resultados físicos, mentales y energéticos en poblaciones adultas sanas y en situaciones especiales de riesgo (estado nutricional subóptimo/síntomas subclínicos al inicio del estudio). Métodos: se realizaron búsquedas en PubMed de ensayos controlados aleatorios relevantes hasta enero 2020. Resultados: en total se identificaron 136 publicaciones. En los siete estudios aleatorizados, doble ciego y controlados con placebo considerados elegibles para la inclusión, la suplementación en poblaciones sanas mostró predominantemente mejoras en la percepción del estrés, la resistencia física, la concentración y la salud mental general, así como una reducción significativa de la ansiedad y mejoras en la vitalidad según la autoevaluación de los participantes. Sin embargo, no todos estos resultados fueron significativos y la corrección estadística para múltiples resultados no se empleó habitualmente. Los estudios sobre el mapeo cerebral después de la suplementación, indicaron un aumento de la actividad funcional en las regiones del cerebro relacionadas con el procesamiento de la atención, el control ejecutivo y la memoria de trabajo durante tareas cognitivas. Conclusiones: si bien ciertamente existe la necesidad de realizar más estudios sobre los beneficios neurocognitivos y físicos de la suplementación con micronutrientes, esta revisión proporciona evidencia en general sobre los beneficios de un suplemento multivitamínico/mineral del complejo B en dosis altas, en poblaciones sanas y en situaciones de riesgo, en términos de resultados físicos, mentales y energéticos.

Therapeutic Opportunities for Food Supplements in Neurodegenerative Disease and Depression.

Emerging evidence is showing nutrition as a crucial factor in the high prevalence and incidence of neurodegenerative mental disorders. Preventive interventions on neuroinflammation seem to be able to interfere with neurodegeneration. Supplementation of essential nutrients, such as long-chain-polyunsaturated fatty acids, vitamin E and mineral elements, may minimize inflammation, enhancing antioxidative defense, and lowering the risk and incidence of age-related diseases, such as cardiovascular diseases and neurodegenerative diseases. This manuscript reviews the current evidence on the role of neuroinflammation in the pathophysiology of neurodegenerative and mental disorders, and preventive strategies for food supplementation in these neuropsychiatric diseases. Dietary supplementation-based strategies have been demonstrated to be effective in subjects with mild cognitive impairment, while weaker results have been obtained in patients with advance neurodegenerative disease. Adjunctive supplementation has also been demonstrated to improve depression, this being of marked benefit considering the comorbidity between cognitive impairment/dementia and depression. Further research is needed to improve the prescriptive precision of supplementation in patients, and to better understand potential interactions with clinical and pharmacokinetic factors.

The effect of vitamin C supplementation on mood status in adults: a systematic review and meta-analysis of randomized controlled clinical trials.

OBJECTIVE: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to clarify the effect of vitamin C supplementation on mood in both depressed and non-depressed populations. METHODS: A systematic search of PubMed, EMBASE, ISI web of science and Scopus databases was conducted, from inception to 1 March 2020. Random-effects meta-analyses were used to estimate the effect size (as Hedge's g) of vitamin C supplementation on depressive symptoms. RESULTS: Finding from 10 trials with 836 participants revealed no significant improvement in mood status in overall analysis (n = 10, Hedge's g = 0.09; 95% confidence interval: -0.15 to 0.33; P = 0.465). However, subgroup analysis showed beneficial effects of vitamin C supplementation in patients who were not prescribed antidepressants (subclinical depressed) (n = 5, Hedge's g: -0.18; 95% CI: -0.35, -0.01, P = 0.041; I2 = 0.00%,). CONCLUSIONS: Although no significant effect on mood status was observed in overall population, this meta-analysis tentatively suggests that vitamin C may produce mood-elevating effects in patients with subclinical depression. Further research is recommended to reach a firm conclusion. PROTOCOL REGISTRATION: The study protocol was registered in the international prospective register of systematic reviews database (http://www.crd.york.ac.uk/PROSPERO, registration no: CRD42018086677).

Pyroluria: Fact or Fiction?

Objective: The term "Mauve factor" (pyrroluria) dates back to 1958 when Dr. Abram Hoffer defined the condition as elevated levels of pyrroles in the urine, currently called hydroxyhemepyrrolin-2-one (HPL). It was suggested that the raised pyrrole levels lead to depletions in zinc and vitamin B6, which, in turn, were hypothesized to result in a range of psychiatric disorders, such as schizophrenia, anxiety, and depression. Treatment implications are supplementation with zinc and B6. This article aimed to review the scientific literature associating pyrroluria with psychiatric symptoms, explore the validity of HPL testing, explore the role of nutrients as treatment options for pyrroluria, and discuss future research directions. Methods: A PRISMA review was conducted using search results from electronic databases PubMed, MEDLINE, PsycINFO, EMBASE from inception to February 2020 using the following keywords: hydroxyhemepyryrrolin (HPL), kryptopyrrole (KP), mauve factor, pyroluria, pyrroluria, monopyrroles. Article reference lists were also scanned and included where relevant. Results: Seventy-three articles were identified of which only three studies identified significantly higher HPL levels in a psychiatric population compared with controls, and there were no placebo-controlled treatment trials directed at pyrroluria. The other 13 clinical studies either showed no association or did not provide adequate data to show group differences in HPL levels. Despite an extensive history of practitioners diagnosing and treating a wide variety of mental health conditions associated with pyrroluria as well as clinical observations of elevated HPL being associated with psychiatric disorders, there was no clear research that showed the following: (1) elevated HPL is robustly associated with increased mental health symptoms, (2) elevated HPL in urine is associated with increased urine excretion of zinc and B6, and (3) high-dose zinc and B6 are an efficacious treatment for mental health problems associated with elevated HPL. Conclusions: Elevated HPL is a clinically observed, but poorly researched biomarker with unclear associations with mental disorders. Based on current evidence, HPL testing is not recommended as a screening or treatment tool. Further research is required in the following areas: establishment of which specific clinical populations exhibit elevated HPL, validation of the chemistry and validity of testing, and controlled trials to establish efficacy of high-dose zinc and B6 as treatment of elevated pyrroles.

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.

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.