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

Figures & data

Table 1. Adapted from the WFSBP Grading system (grades of recommendations).

Recommendation FOR or AGAINST using the intervention	Grade	Level of Evidence (LoE)
Recommended	+++	‘A’ LoE with robust positive data meta-analyses or meta-reviews involving underpinning RCTs, with ROBUST, ACCEPTABLE, or FAIR safety/tolerability
Provisionally Recommended	++	‘A’ LoE with mainly positive data from either meta-analyses or meta-reviews or ≥2 RCTs of good or average quality, with ROBUST, ACCEPTABLE, or FAIR safety/tolerability
Weakly Recommended	+	‘A’ LoE mixture of (primarily) positive and negative data from either meta-analyses or meta-reviews or ≥2 RCTs of good or average underpinning quality, tending towards positive findings, with ROBUST, ACCEPTABLE, or FAIR safety/tolerability
Not Currently Recommended	+/−	‘A’ LoE mixture of positive and negative data from either meta-analyses or meta-reviews or ≥2 RCTs of good or average or weak underpinning quality, with ROBUST, ACCEPTABLE, or FAIR tolerability
Not Recommended	−	‘A’ LoE with robust negative data from meta-analyses or meta-reviews or ≥2 RCTs and/or POOR safety/tolerability

Table 2. Guidelines Search Terms.

Participants (any mental disorder)

Depression OR depressive OR mental illness* OR mental disorder* OR mood disorder* OR affective disorder* OR anxiety OR panic disorder OR obsessive compulsive OR ADHD OR attention deficit OR attentional deficit OR phobia OR bipolar type OR bipolar disorder* OR psychosis OR psychotic OR schizophr* OR antipsychotic* OR post traumatic* OR personality disorder* OR stress disorder* OR dissociative disorder*

Interventions (any nutrient or nutraceutical)

Vitamin* OR mineral* OR nutrient* OR food supplement* OR meal replacement* OR nutritional supplement* OR health supplement* OR multivitamin* OR omega 3 OR fish oil* OR alpha lipoic acid OR alpha linolenic acid OR alpha linoleic acid OR eicosapentaenoic OR docosahexaenoic OR fatty acid* OR amino acid* OR taurine OR S-adenosyl methionine OR creatine OR acetylcysteine OR cysteine OR probiotic* OR tryptophan OR tocopherol OR alphatocopherol OR carotene OR retinol OR thiamine OR riboflavin OR niacin OR niacinamide OR nicotinic acid OR pantothenic OR pyridox* OR biotin OR methylfolate OR 5-MTH* OR levomefolic acid OR folate OR folinic acid OR folic acid OR inositol OR cyanocobalamin OR methylcobalamin OR cobalamin OR ascorbic acid OR cholecalciferol OR iron OR ferrous OR tocopherols OR trace element OR calcium OR phosphorus OR magnesium OR potassium OR manganese OR zinc OR selenium OR boron OR chromium OR lycopene OR isoflav* OR flavonoid* OR bioflavonoid* OR micronutrient OR carnitine OR herbal OR herbal medicine OR plant medicine OR phytomedicine OR supplement OR st John’s wort OR kava OR ginseng OR saffron OR curcumin OR valerian OR ginkgo OR rhodiola OR Bacopa monniera OR Centella asiatica OR Crocus sativus OR Curcuma longa OR Hypericum perforatum OR Galphimia OR Ginkgo biloba OR Lavandula OR Matricaria spp. OR Panax ginseng OR Passiflora incarnata OR Piper methysticum OR Rhodiola rosea OR Valeriana OR Withania somnifera

Comparator (placebo-controlled trials)

Random* OR Placebo OR Control* or Adjunc* or Clinical Trial*

Outcomes (any from meta-analyses or randomised controlled trials or systematic reviews)

Meta-analy* OR Metaanaly* OR Clinical Trial OR RCT* OR systematic review

Table 3. Intervention type, and mental disorders covered

Intervention type	Mental health disorder	Intervention
Nutraceuticals	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-HTP, 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
Phytoceuticals	Mood disorders	St John’s wort, saffron, curcumin, rhodiola, and lavender
	Anxiety disorders	Lavender, kava, ashwagandha, galphimia, and chamomile
	Psychotic disorders	Ginkgo
	ADHD	Ginkgo

Table 4. Depression (Unipolar and Bipolar).

Nutraceutical	Indications	Level of evidence	Grade* (+ or −)	Suggested dosage per day	Tolerability/ safety	Clinical advice	References
Omega-3	MDD (Adj) (Mono)	A (Meta + 5 RCTs)	+++ +/−	1 g–2 g of EPA or mixed EPA/DHA	ROBUST Caution with blood-thinning medication; Potential GI upset	Potentially more effective adjunctively with antidepressants, and in raised inflammatory markers and/or obesity	MDD: (Mocking et al. 2016; Gabbay et al. 2018; Carney et al. 2019; Fristad et al. 2019; Chang et al. 2020; Jana et al. 2020)
	BD (Adj)	A (Meta + 3 RCTs)	+				BD: (Murphy et al. 2012; Sarris, Mischoulon, et al. 2011; Wozniak et al. 2015; Shakeri et al. 2016)
Vitamin D	MDD (Adj/Mono)	A (Meta + 2 RCTs)	+	1500 IU– 4000 IU	ROBUST Considered safe	Unlikely to be of benefit in those with sufficient skin exposure to sufficient non-winter sunlight and/or dietary intake	(Alghamdi et al. 2020; Cheng et al. 2020; Vellekkatt et al. 2020)
Probiotics	MDD (Adj/Mono)	A (Meta)	++	1–10 billion colony forming units (varying strains)	ROBUST Considered safe	The most appropriate probiotics strains for depression have not been confirmed, certain and variations are potentially more beneficial depending on an individual’s genetics and diet	(Sanada et al. 2020)
Zinc	MDD (Adj)	A (Meta)	++	∼25 mg elemental	ACCEPTABLE Considered safe below 40mg per day, although nausea may occur on an empty stomach	May have a specialised use in cases of comorbid lowered immune response or raised inflammation, or high oxidative stress (especially if dietary deficient)	(Schefft et al. 2017)
Folate-based compounds	MDD (Adj)	A (Meta)		Methylfolate (15 mg)	FAIR Fairly safe, however larger doses of synthetic folic acid have been linked to very slight increase of some cancers	Methylfolate potentially more effective due to the metabolic bypass of the T677C polymorphism	(Bedson et al. 2014; Roberts et al. 2018)
	Folic acid		−
	MTHF/acid		++
S-adenosyl methionine	MDD	A (5 RCTs)		800 mg–3200 mg	ACCEPTABLE	SAMe is an unstable compound and enteric coating and storage in blister packs under refrigeration may be advised	(Pancheri et al. 2002; George I. Papakostas et al. 2010; Mischoulon et al. 2014; Sarris et al. 2018; Sarris, Murphy, et al. 2020)
	(Mono) (Adjunctive)		+/− +		A safe compound, however, caution is advised in bipolar disorder
Vitamin C	MDD (Adj)	A (2 RCTs)	+/−	∼1 g	ROBUST Considered safe, however excess doses may cause gastrointestinal disturbance (e.g. diarrhea)	While evidence is not supportive, there may be a potential role in cases of Vit C deficiency or comorbid immune system deficiency	(Amr et al. 2013; Sahraian et al. 2015)
Tryptophan & 5-HTP	MDD (Adj/Mono)	A (Meta +1 RCT)	+/−	∼1 g (tryptophan), 50 mg–200 mg (5-HTP)	ACCEPTABLE Caution is advised in co-use with antidepressants	Older research showing mixed efficacy. 5-HTP a preferred form as a precursor of serotonin. May be of benefit in the evening for comorbid insomnia	(Levitan et al. 2000; Shaw et al. 2002)
Creatine	MDD (Adj/Mono)	A (2 RCTs)	+/−	5 g	FAIR Caution in excess doses and in people with kidney issues	May have a role in people with MDD and comorbid fatigue	(Lyoo et al. 2012, Nemets and Levine 2013)
Inositol	MDD (Adj)	A (Meta)	−	∼12 g	ACCEPTABLE Considered safe, however may cause gastrointestinal discomfort at high doses	Not effective for use in MDD	(Mukai et al. 2014)
Magnesium	MDD (Adj)	A (2 RCTs)	−	100–400 mg elemental	ROBUST Considered safe	While evidence is not supportive for use in MDD, there may still be an application in deficiency	(Mehdi, Atlas et al. 2017; Ryszewska-Pokraśniewicz et al. 2018)
N-acetyl cysteine	BD (Adj)	A (4 RCTs)	+/−	1g–3 g	ACCEPTABLE Considered safe	May have a specialised use across a range of comorbid psychiatric disorders, especially in cases of high oxidative stress	(Berk et al. 2008, 2012; Bauer et al. 2017; Ellegaard et al. 2019)
Phytoceutical	Indications	Level of evidence	Grade (+ or −)	Suggested Dosage per Day	Safety	Clinical Advice	References
St John’s wort	Mono	A (Meta)	+++	600 mg–1800 mg (standardised to hypericin 0.2–0.3% AND/OR 5–6% hyperforin)	ACCEPTABLE Caution for use in Bipolar Disorder. May cause photosensitivity. Do not use with SSRIs or SNRIs due to potential of serotonin syndrome. Hyperforin-rich extracts may reduce serum levels of many drugs	Use of quality standardised extracts is vital to be confident of replicated effects shown in RCTs	(Apaydin et al. 2016)
Saffron	MDD (Adj/Mono)	A (Meta)	++	30 mg per day of stigma (standardised to safranal or crocin isomers)	ACCEPTABLE Considered safe, aside from potential minor adverse effects e.g. gastrointestinal symptoms, increased stimulation	Stigma/petal combinations may still provide antidepressant effects (and be much cheaper than stigma alone)	(Marx et al. 2019)
Curcumin	MDD (Adj/Mono)	A (Meta)	++	500 mg–1000 mg (curcumin)	ACCEPTABLE Considered safe	Potential adjuvant benefit in comorbid inflammatory disorders. Bioavailable forms are advised e.g. liposomal	(Fusar-Poli et al. 2020)
Rhodiola	MDD (Adj/Mono)	A (2 RCTs)	+/−	340–680 mg (standardised to rosvarin)	ACCEPTABLE Considered safe	Potential role in depression co-occurring with fatigue	(Darbinyan et al. 2007; Mao et al. 2015)
Lavender	MDD (Adj/Mono)	A (3 RCTs)	++	80 mg–160 mg per day of a specialised oil (in capsule form) or 500 mg–1.5 g of dried flower (standardised to linalool)	ACCEPTABLE Considered safe	Use of standardised capsule formulations advised over tea preparations of unknown quality	(Akhondzadeh et al. 2003; Nikfarjam et al. 2013, 2017)

*= Recommendation level; Grades= +++, ++, +, ± −Adj: Adjunctive; Mono: Monotherapy; MDD: Major Depressive Disorder; BD: Bipolar Disorder; Meta: Meta-analysis level data; RCTs: two or more randomised controlled trials; ROBUST, ACCEPTABLE, POOR: level of safety and tolerability as assessed via available clinical trial data, regulatory agencies, and pharmacovigilance databases.

Table 5. Anxiety disorders.

Nutraceutical	Indications	Level of evidence	Grade* (+ or −)	Suggested dosage per day	Tolerability/ safety	Clinical advice	References
N-acetyl cysteine	OCD (Adj/Mono)	A (Meta)	+	2 g–3 g	ACCEPTABLE Considered safe	May have a specialised use across a range of comorbid psychiatric disorders, especially in cases of high oxidative stress	OCD: (Gadallah et al. 2020; Li et al. 2020)
	Trichotillomania	A (RCTs)	+/−	2 g–3 g			Trichotillomania: (Grant et al. 2009; Bloch et al. 2013)
Phytoceutical	Indications	Level of Evidence	Grade (+ or −)	Suggested Dosage per Day^	Tolerability/ Safety	Clinical Advice	References
Kava	GAD (Mono)	A (Meta + 2 RCTs)	−	60mg-250mg of kavalactones	FAIR Caution for use in people with liver issues, and avoidance with alcohol and benzodiazepines	While not effective for GAD, potential use for acute or short-term management of general anxiety symptoms supported Important to recommend only the use of ‘noble’ varieties of the rootstock of the plant standardised to a sufficient level of kavalactones	(Barić et al. 2018; Kuchta et al. 2018; Sarris, Byrne, et al. 2020)
Ashwagandha	GAD (Adj/Mono)	A (3 RCTs)	++	300 mg–600 mg (standardised to 5% withanolides)	ACCEPTABLE Considered safe	May be of additional benefit in improving cognition in BD	(Andrade et al. 2000; Sud Khyati and Anup 2013; Fuladi et al. 2020)
Galphimia	GAD (Mono)	A (2 RCTs)	+	350 mg–700 mg (standardised to galphimine-B)	FAIR Considered safe	Not commonly used outside South America, sourcing could be an issue	(Herrera-Arellano et al. 2007, 2012)
Chamomile	GAD (Adj/Mono)	A (2 RCTs)	+/−	220 mg–1500 mg (potentially standardised to chrysin or apigenin)	ROBUST Robust safety data	Standardised extracts preferable to teas of unknown quality	(Amsterdam et al. 2009; Mao et al. 2016)
Lavender	GAD (Adj/Mono)	A (3 RCTs)	++	80 mg–160 mg per day of a specialised oil (in capsule form) or 500 mg–1.5 g of dried flower (standardised to linalool)	ACCEPTABLE Considered safe	Highly standardised essential oil based extracts potentially more effective than general dried raw material	(Kasper et al. 2014, 2015; Farshbaf-Khalili et al. 2018)

*= Recommendation level; Grades= +++, ++, +, ± − ; Adj: Adjunctive; Mono: Monotherapy; GAD: Generalised Anxiety Disorder; Meta: Meta-analysis level data; RCTs: two or more randomised controlled trials; ROBUST, ACCEPTABLE, POOR: level of safety and tolerability as assessed via available clinical trial data, regulatory agencies, and pharmacovigilance databases.

Table 6. Schizophrenia.

Nutraceutical	Indications	Level of evidence	Grade* (+ or −)	Suggested Dosage per Day	Tolerability/ Safety	Clinical Advice	References
Omega-3	Schz (Adj)	A (Meta) + 1 RCT	−	1 g–2 g of EPA or mixed EPA/DHA	ROBUST Caution with blood-thinning medication; Potential GI upset	Potentially more effective in raised inflammatory markers and in obesity (especially metabolic issues from antipsychotics)	(Çakici et al. 2019; Qiao et al. 2020)
Vitamin D	Schz (Adj)	A 2 RCTs	−	1500 IU–4000 IU	ROBUST Considered safe	Unlikely to be of benefit in those with sufficient skin exposure to sufficient non-winter sunlight and/or dietary intake	(Sheikhmoonesi et al. 2016; Krivoy et al. 2017)
N-acetyl cysteine	Schz (Adj)	A (Meta)	++	1 g–3 g	ACCEPTABLE Considered safe	May have a specialised use across a range of comorbid psychiatric disorders, especially in cases of high oxidative stress	(Yolland et al. 2020)
Folate-based compounds	Schz (Adj)	A (Meta)	++	Methylfolate (1–15 mg)	FAIR Fairly safe, however larger doses of synthetic folic acid have been linked to very slight increase of some cancers	5-MTHF potentially more effective due to the metabolic bypass of the T677C polymorphism	(Sakuma et al. 2018)
Phytoceutical	Indications	Level of evidence	Grade (+ or −)	Suggested dosage per day	Safety	Clinical advice	References
Ginkgo	Schz (Adj)	A (Meta)	+	120 mg–360 mg (2–3% ginkgoflavones)	ACCEPTABLE Caution with blood-thinning medication	Potential role for negative symptoms, tardive dyskinesia, and for enhancing cognition in this population	(Chen et al. 2015)

*= Recommendation level; Grades= +++, ++, +, ± − ; Adj: Adjunctive; Mono: Monotherapy; Schz: Schizophrenia; Meta: Meta-analysis level data; RCTs: two or more randomised controlled trials; ROBUST, ACCEPTABLE, POOR: level of safety and tolerability as assessed via available clinical trial data, regulatory agencies, and pharmacovigilance databases

Table 7. ADHD treatment guidelines.

Nutraceutical	Indications	Level of evidence	Grade* (+ or − )	Suggested dosage per Day^	Tolerability/ safety	Clinical advice	References
Omega-3 Fatty acids	ADHD (Mono/Adj)	A (Meta + 4 new RCTs) Children	+/−	120 mg–1200 mg	ROBUST Robust safety data	May be of benefit in deficiency; higher EPA preparations potentially more effective	( Cornu et al. 2018; Crippa et al. 2019; Mohammadzadeh et al. 2019; Rodriguez et al. 2019; Chang et al. 2020 )
Omega-9 Fatty Acids (Efamol)	ADHD (Mono/Adj)	A (2 RCTs) Children	−	2 g–3 g	ROBUST Robust safety data	Not recommended for ADHD. Sufficient omega-9s highly available in most diets	(Aman et al. 1987; Arnold et al. 1989)
Micronutrient formula	ADHD (Mono)	A (Meta involving 2 RCTs: 1 Adult 1 Child)	+	Micronutrient formula (8–12 capsules)	ACCEPTABLE Considered safe, has been studied used for decades	This particular micronutrient formula’s efficacy cannot necessarily be extended to other multivitamins	(Rucklidge et al. 2014, 2018; Johnstone et al. 2020)
Vitamin D	ADHD (Mono/Adj)	A (Meta) Mixed	+	1500–4000 IU	ROBUST Robust safety data	Unlikely to be of benefit in those with sufficient skin exposure to sufficient non-winter sunlight and/or dietary intake	(Gan et al. 2019)
Acetyl-L-Carnitine	ADHD (Mono/Adj)	A (2 RCTs) Children	−	1 g–3 g	ACCEPTABLE Fair safety data	Not effective for ADHD	(Arnold et al. 2007; Abbasi et al. 2011)
Zinc	ADHD (Adj)	A (5 RCTs) Children	+/−	15 mg–40 mg (elemental)	ACCEPTABLE Considered safe below 40 mg per day (for adults), although nausea may occur on an empty stomach	May have a specialised use in cases of comorbid lowered immune response or raised inflammation, or high oxidative stress (especially if dietary deficient)	(Akhondzadeh et al. 2004; Bilici et al. 2004; Arnold et al. 2011; Zamora et al. 2011; Noorazar et al. 2020)
Phytoceutical	Indications	Level of Evidence	Grade (+ or − )	Suggested Dosage per Day^	Tolerability/ Safety	Clinical Advice	References
Ginkgo	ADHD (Mono/Adj)	A (2 RCTs) Children	+/−	80 mg–120 mg (2–3% of ginkgoflavones)	ACCEPTABLE Caution with blood-thinning medication	Mixed evidence for ADHD. May potentially improve some elements of impaired cognition	(Salehi et al. 2010; Shakibaei et al. 2015)

*= Recommendation level; Grades= +++, ++, +, ± − Adj: Adjunctive; Mono: Monotherapy; ADHD: Attention Hyperactivity Deficit Disorder ^=Per Day (based on age and weight for children); Meta:Meta-analysis level data; RCTs: two or more randomised controlled trials; ROBUST, ACCEPTABLE, POOR: level of safety or tolerability as assessed via available clinical trial data, regulatory agencies, and pharmacovigilance databases.

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