Clinical guidelines for treating psychiatric disorders with nutraceuticals and phytoceuticals

An international taskforce assembled by the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Disorders (CANMAT) has issued global guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals, updating previous guidelines published by CANMAT in 2016. Nutraceuticals and phytoceuticals are commonly used for the treatment of mental disorders and healthcare providers need current evidence-based guidance on their use. The WFSBP/CANMAT guidelines use an evidence-informed approach to assist clinicians in making decisions around the use of nutraceuticals and phytoceuticals as monotherapy or adjunctive therapy in the treatment of major psychiatric disorders (mood disorders, anxiety disorders, psychotic disorders, attention deficit hyperactivity disorder [ADHD]). They also provide brief information on nutraceutical/phytoceutical safety and tolerability, drug interactions, and considerations for use in specialized populations. The term nutraceutical refers to a nutrient-based natural product, while a phytoceutical refers to a plant-based natural product, both produced by pharmaceutical good manufacturing practices. The WFSBP/CANMAT guidelines use the following grading system based on the level of evidence: Recommended (+++)—robust positive data Provisionally Recommended (++)—mainly positive data Weakly Recommended (+)—mixture of (primarily) positive and negative data Not Currently Recommended (+/-)—mixture of positive and negative data Not Recommended (-)—robust negative data. Nutraceuticals The guidelines evaluated evidence for using several nutraceuticals for treatment of the psychiatric disorders specified below: Mood disorders: Omega-3 fatty acids (in particular eicosapentaenoic acid: EPA), vitamin D, N-acetyl cysteine, probiotics, zinc, folate-based compounds, S-adenosyl-methionine, vitamin C, tryptophan and 5-hydroxytryptophan, creatine, inositol, and magnesium Anxiety disorders: N-acetyl cysteine Psychotic disorders: Omega-3 fatty acids, vitamin D, N-acetyl cysteine, and folate-based compounds ADHD: Vitamin D, zinc, folate-based compounds, omega-3 and omega-9 fatty acids, broad-spectrum micronutrients, and acetyl-L-carnitine Omega-3 fatty acids were the only nutraceuticals to receive a “Recommended (+++)” rating for treatment of a psychiatric disorder. They are “Recommended” for the treatment of major depressive disorder as an adjunctive therapy, but are “Not Currently Recommended” for monotherapy use. No nutraceutical received a “Recommended (+++)” rating for treatment of anxiety disorders, schizophrenia or ADHD. Read: QUIZ: Test your knowledge of medications for ADHD Statements regarding the efficacy of specific nutraceuticals in the treatment of psychiatric disorders are summarized below: Acetyl-L-carnitine (ALC) at doses of 1–3 g/day is “Not Recommended” for adjunctive or monotherapy use in ADHD in children. Creatine (5 g/day) is “Not Currently Recommended” for adjunctive or monotherapy use in major depressive disorder. Ginkgo extract at doses of 120–360 mg (50:1 standardized extract) is “Weakly Recommended” for adjunctive use in schizophrenia (primarily for negative symptoms); and is “Not Currently Recommended” for monotherapy or adjunctive use in ADHD in children at doses of 80–120 mg (50:1 standardized extract). Inositol at doses up to 12 g/day is “Not Recommended” for adjunctive or monotherapy use in major depressive disorder. Magnesium at doses of 100–400 mg (elemental)/day is “Not Recommended” for adjunctive or monotherapy use in major depressive disorder. Methylfolate (15 mg/day) is “Provisionally Recommended” for adjunctive use in major depressive disorder (folic acid is “Not Recommended”). Methylfolate (1–15 mg/day) is “Provisionally Recommended” for adjunctive use in schizophrenia (primarily for negative symptoms). Micronutrient formula: A broad-spectrum micronutrient formula (13 vitamins and 15 minerals) taken as 8–12 capsules per day is “Weakly Recommended” for monotherapy use in ADHD (children and adults). N-acetyl cysteine (NAC) at doses of 1–3 g/day is “Not Currently Recommended” for adjunctive use in bipolar disorder; “Weakly Recommended” for adjunctive use in obsessive compulsive disorder at doses of 2–3 g/day; “Not Currently Recommended” for adjunctive use in trichotillomania at doses of 2–3 g/day; and “Provisionally Recommended” for adjunctive use in schizophrenia (primarily for negative symptoms) at doses of 1–3 g/day. Omega-3 fatty acids at doses standardized to 1–2 g of EPA are “Recommended” for treatment of major depressive disorder (as an adjunctive therapy); “Weakly Recommended” for adjunctive use in bipolar depression; “Not Recommended” for adjunctive or monotherapy use in schizophrenia; “Not Currently Recommended” for monotherapy or adjunctive use in ADHD in children at doses of 120–1200 mg; and “Not Recommended” for monotherapy or adjunctive use in ADHD in children at doses of 2–3 g. Probiotic strains (e.g., Lactobacillus and Bifidobacterium spp.) at doses of 1–10 billion units/day are “Provisionally Recommended” for adjunctive use and “Weakly Recommended” for monotherapy use in major depressive disorder. S-adenosyl methionine (SAMe) at doses of 800 mg per day is “Not Currently Recommended” for monotherapy use in major depressive disorder; and “Weakly Recommended” for adjunctive use in major depressive disorder at doses of 1600–3200 mg/day. Tryptophan at doses of up to 1 g per day (or 5-hydroxytryptophan at 50 mg–200 mg/day) is “Not Currently Recommended” for adjunctive or monotherapy use in major depressive disorder. Vitamin C at doses of approximately 1 g per day is “Not Currently Recommended” for adjunctive or monotherapy use in major depressive disorder. Vitamin D at doses of 1500–4000 IU per day is “Weakly Recommended” for adjunctive or monotherapy use in major depressive disorder; “Not Recommended” for adjunctive use in schizophrenia; and “Weakly Recommended” for adjunctive use in ADHD in children. Zinc at doses of approximately 25 mg per day is “Provisionally Recommended” for adjunctive use in major depressive disorder; and “Not Currently Recommended” for monotherapy or adjunctive use in ADHD in children at doses of 15–40 mg (elemental)/day, depending on weight/age. Phytoceuticals The guidelines evaluated evidence for several phytoceuticals in the treatment of the following psychiatric disorders: Mood disorders: St John’s wort, saffron, curcumin, rhodiola, and lavender Anxiety disorders: Lavender, kava, ashwagandha, galphimia, and chamomile Psychotic disorders: Ginkgo ADHD: Ginkgo St John’s wort (as monotherapy) was the only phytoceutical to receive a “Recommended (+++)” rating for treatment of a psychiatric disorder, being “Recommended” as a monotherapy for the treatment of mild to moderate depression. No phytoceutical received a “Recommended” rating for treatment of anxiety disorders, schizophrenia or ADHD. Read: Ketamine may be useful for acute treatment of severe suicidal ideation Statements regarding the efficacy of specific phytoceuticals in the treatment of psychiatric disorders are summarized below: Ashwagandha root extract at doses of 300–600 mg/day (standardized to 5% withanolides) is “Provisionally Recommended” for monotherapy or adjunctive use in generalized anxiety disorder. Chamomile flowers standardized at doses of 220–1500 mg/day (depending on standardization of volatile compounds or apigenin or chrysin) is “Not Currently Recommended” for monotherapy or adjunctive use in generalized anxiety disorder. Curcumin extract at a dose of approximately 500–1000 mg/day (depending on extract) is “Provisionally Recommended” for monotherapy or adjunctive use in mild to moderate depression. Galphimia aerial parts extract at doses of 350–700 mg twice daily (standardized to galphimine B) is “Weakly Recommended” for monotherapy use in generalized anxiety disorder. Kava rootstock extracts standardized to kavalactones at 60–250 mg is “Not Recommended” for adjunctive or monotherapy use for generalized anxiety disorder. Lavender at doses of 80–160 mg of essential oil/day (in the form of soft gels), or 500 mg to 1.5 g of dried flower twice daily (preferably in the form of standardized formulations) is “Weakly Recommended” for monotherapy or adjunctive use in major depressive disorder. It is also “Provisionally Recommended” for monotherapy or adjunctive use in generalized anxiety disorder at doses of 80–160 mg/day of a specialized oil (in capsule form) or 500 mg to 1.5 g of dried flower twice daily (preferably in the form of standardized formulations). Rhodiola root at a dose of approximately 340–680 mg (1–3 times daily depending on extract) is “Not Currently Recommended” for monotherapy or adjunctive use in major depressive disorder. Saffron at a dose of approximately 30 mg of the stigma, or standardized to safranal or crocin isomers (1–3 times daily depending on extract) is “Provisionally Recommended” for monotherapy or adjunctive use in mild to moderate depression. St John’s wort is “Recommended” as monotherapy for the treatment of mild to moderate depression. It should be given as St John’s wort flowers at doses of 600–1800 mg/day (3:1–7:1 extract depending on product), standardized to a dose of approximately 0.2%–0.3% hypericin and/or 5%–6% hyperforin (1–3 times daily depending on extract). The WFSBP/CANMAT guidelines note that more than two dozen nutraceuticals and phytoceuticals have been evaluated in rigorous double-blind randomized controlled trials. However, methodological flaws were encountered in many other studies, which limit the replicability and potential clinical confidence in the findings. These flaws included small sample sizes, markedly varied doses, insufficient information about trial designs (especially regarding blinding processes), and failure to standardize active constituents (in some phytoceutical studies). Therefore, several agents reviewed in the WFSBP/CANMAT guidelines still need to be investigated in large multicentre randomized controlled trials to further evaluate their efficacy and safety. The authors urge caution when prescribing or recommending any nutraceutical and/or phytoceutical as a monotherapy, particularly in severe psychiatric disorders; these agents should only be used in conjunction with conventional care. However, a range of nutraceuticals and phytoceuticals may be safely used to augment conventional therapies, to enhance treatment outcomes. Reference 1. Sarrishttps J, Ravindrand A, Yatham LN, et al. 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. World J Biol Psychiatry 2022; Mar 21;1-32. (accessed April 11, 2022).

Clinical guidelines for treating psychiatric disorders with nutraceuticals and phytoceuticals

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