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

Abstract

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.

Keywords:

• Nutrients
• herbal medicines
• schizophrenia
• ADHD
• affective disorders

Statement of interest

JS has conducted a range of clinical trials on nutraceuticals or phytoceuticals, and has received either presentation honoraria, travel support, clinical trial grants, book royalties, or independent consultancy payments from nutraceutical/phytoceutical companies: Integria Healthcare & MediHerb, Pfizer, Scius Health, Key Pharmaceuticals, Taki Mai, Fiji Kava, FIT-BioCeuticals, Blackmores, Soho-Flordis, Healthworld, HealthEd, HealthMasters, Kantar Consulting, Angelini Pharmaceuticals, Grunbiotics, Polistudium, Australian Natural Therapeutics Group, Research Reviews, Elsevier, Chaminade University, International Society for Affective Disorders, Complementary Medicines Australia, SPRIM, Terry White Chemists, ANS, Society for Medicinal Plant and Natural Product Research, Sanofi-Aventis, Omega-3 Centre, the National Health and Medical Research Council, CR Roper Fellowship. MB has received Grant/Research Support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, Medical Benefits Fund, National Health and Medical Research Council, Medical Research Futures Fund, Beyond Blue, Rotary Health, A2 milk company, Meat and Livestock Board, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Abbot, Astra Zeneca, Janssen and Janssen, Lundbeck and Merck and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Janssen and Janssen, Lundbeck Merck, Pfizer and Servier. MB is supported by a NHMRC Senior Principal Research Fellowship [1156072]. LNY has received honoraria or research grants from Abbvie, Allergan, CANMAT, DSP, Intracellular therapies, Lundbeck, Merck, Otsuka, and Sanofi. AR has received research grants and honoraria from Abbvie, CANMAT, Janssen, Otsuka, and CIHR, Templeton Foundation and Grand Challenges Canada. WM is currently funded by an Alfred Deakin Postdoctoral Research Fellowship and a Multiple Sclerosis Research Australia early-career fellowship. Wolfgang has previously received funding from the NHMRC, Clifford Craig Foundation, Cancer Council Queensland and university grants/fellowships from La Trobe University, Deakin University, University of Queensland, and Bond University, received industry funding and has attended events funded by Cobram Estate Pty. Ltd, received travel funding from Nutrition Society of Australia, received consultancy funding from Nutrition Research Australia, and has received speakers honoraria from The Cancer Council Queensland and the Princess Alexandra Research Foundation. JR has received academic funding for conducting broad-spectrum micronutrient research. DM has received research support from Nordic Naturals and heckel medizintechnik GmbH. He has received honoraria for speaking from the Massachusetts General Hospital Psychiatry Academy, Harvard Blog, and PeerPoint Medical Education Institute, LLC. He also works with the MGH Clinical Trials Network and Institute (CTNI), which has received research funding from multiple pharmaceutical companies and NIMH. BH has participated in advisory boards, received honoraria from Servier, and received research funding from Servier, Lundbeck, Deakin University, Cannabis Science Inc, HG&H Pharmaceuticals and the South African Medical Research Council. OMD is a R.D. Wright Biomedical NHMRC Career Development Fellow [APP1145634] and has received grant support from the Brain and Behaviour Foundation, Simons Autism Foundation, Stanley Medical Research Institute, Deakin University, Lilly, NHMRC and ASBDD/Servier. She has also received in kind support from BioMedica Nutraceuticals, NutritionCare and Bioceuticals. JSS has previously served on the scientific advisory board of Bioceuticals. HC has received Research Support from Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany. DN has received personal fees from Startia, Inc., en-power, Inc., and MD.net, outside the submitted work. CHN has participated as a consultant for Lundbeck, Grunbiotics, Servier, Janssen-Cilag, and Eli Lilly, received research grant support from Lundbeck, and speaker honoraria from Servier, Lundbeck, Sumitomo, Bristol-Myers Squibb, Organon, Eli Lilly, GlaxoSmithKline, Janssen- Cilag, Astra-Zenaca, and Pfizer. MPF Research Support: National Pregnancy Registry for Psychiatric Medications: Alkermes Biopharmaceuticals; Aurobindo Pharma; Auromedics Pharma LLC; Janssen Pharmaceutica; Otsuka Pharmaceuticals; Teva Pharmaceuticals; Sage Therapeutics, Inc.; Sunovion Pharmaceuticals, Inc; Supernus Pharmaceuticals. Past Sponsors: Forest/Actavis/Allergan (2016-2018, declined to sponsor: 2018-Present), AstraZeneca Pharmaceuticals (2009-2014, declined to sponsor: 2014-Present); Ortho-McNeil-Janssen Pharmaceuticals, Inc (2009-2014, declined to sponsor: 2015-Present); Pfizer, Inc. (2009-2011, declined to sponsor: 2012-Present). Other Research Support: As an employee of MGH, Dr. Freeman works with the MGH CTNI, which has had research funding from multiple pharmaceutical companies and NIMH. Advisory/Consulting: Advisory Boards: Eliem, Sage; Independent Data Safety and Monitoring Committee: Janssen (Johnson & Johnson), Novartis; Steering Committee for Educational Activities: Medscape; educational activities: WebMD. RSM has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie, Atai Life Sciences. Dr. Roger McIntyre is a CEO of Braxia Scientific Corp. WM is currently funded by an Alfred Deakin Postdoctoral Research Fellowship and a Multiple Sclerosis Research Australia early-career fellowship. Wolfgang has previously received funding from the NHMRC, Clifford Craig Foundation, Cancer Council Queensland and university grants/fellowships from La Trobe University, Deakin University, University of Queensland, and Bond University, received industry funding and has attended events funded by Cobram Estate Pty. Ltd, received travel funding from Nutrition Society of Australia, received consultancy funding from Nutrition Research Australia, and has received speakers honoraria from The Cancer Council Queensland and the Princess Alexandra Research Foundation. AL has completed several clinical trials on phytoceuticals and has received either presentation honoraria or clinical trial grants from Arjuna Natural Ltd, Dolcas-Biotech LLC, Pharmactive Biotech Products SL, Ixoreal Biomed, Metagenics Australia, EuroPharma Inc, Natural Remedies Pty Ltd, Verdure Sciences Inc, Sabinsa Corporation, Bio-Practica, and Activ’Inside. SS has received funding from the Department of Science and Innovation and the National Research Foundation for the South African Research Chairs Initiative on Posttraumatic Stress Disorder, from the SAMRC South African Medical Research Council (SAMRC) for the SAMRC Unit on the Genomics of Brain Disorders, and from Servier (as national Principal Investigator on a clinical trial). ZJZ has received research grants from Health and Medical Research Fund (HMRF) of the Food and Health Bureau of Hong Kong [No.: 12133711], General Research Fund (GRF) of Research Grant Council of HKSAR [17115017], and National Key R&D Program of China [2018YFC1705801]. KSP Kuan-Pin Su is supported by the following grants: MOST 108-2320-B-039-048, 108-2813-C-039-133-B, 108-2314-B-039-016, 109-2320-B-038-057-MY3, 109-2320-B-039-066, and 110-2321-B-006-004 from the Ministry of Science and Technology, Taiwan; ANHRF109-31 from An Nan Hospital, China Medical University, Tainan, Taiwan; and CMU104-S-16-01, CMU103-BC-4-1, CRS-108-048, DMR-108-216, DMR-109-102, DMR-109-244, DMR-HHC-109-11 and DMR-HCC-109-12 from the China Medical University Hospital, Taichung, Taiwan. SK Dr Kasper has received grants/research support, consulting fees and/or honoraria within the last 3 years; grant/research support from Lundbeck; he has served as a consultant or on advisory boards Celegne, IQVIA, Janssen, Lundbeck, Mundipharma, Recordati, Takeda and Schwabe; and he has served on speakers bureaus for Angelini, Aspen Farmaceutica S.A., Janssen, Krka Pharma, Lundbeck, Medichem Pharmaceuticals Inc., Neuraxpharma, OM Pharma, Pierre Fabre, Sanofi, Servier, Schwabe, Sun Pharma.