<h2>Practice points</h2><ul><li>Vitamin B complex studies show benefits in reducing chronic work stress, perceived stress, anxiety and reduced mental fatigue during intense mental processing7,8,9</li><li> Ashwagandha is an anti-stress14,15 herbal medicine with anxiolytic qualities.17 A specific extract KSM-66 has shown reduction in stress and anxiety as well as reduction in serum cortisol levels15</li><li>Kava may be of benefit in general anxiety disorder (GAD), generalised anxiety-related disorders, and when tapering off benziodiazepines18,19</li><li>Magnesium (Mg) status is associated with subjective anxiety. A systematic review of 18 studies suggested a beneficial effect of Mg on subjective anxiety in anxiety vulnerable-people, however further well-designed randomised controlled trials are required27</li><li>Fish oil (omega-3) - several clinical studies show beneficial effects of omega-3 fatty acids including improved mood profile, increased vigour, reduced anger, and anxiety and depression states28 </li><li>Other herbal medicines useful in stress and anxiety states, include St. John’s wort, valerian, passionflower and sage</li><li>Diet and lifestyle modifications including adopting a diet rich in complex carbohydrate, lean protein and omega-3-rich foods; reducing alcohol, caffeine and nicotine and recommending exercise and mindfulness</li></ul><ul><li> <ul><li> <h2>Description</h2> </li><li> <ul><li>Stress is a normal human response to a threat, however, when associated with high levels of autonomic arousal, erroneous cognitions, and dysfunctional coping strategies, the effects of stress can significantly impact day-to-day living2</li><li>Anxiety is a group of conditions characterised by excessive fears and worries that may be difficult to control.1 It may be accompanied by other overlapping comorbidities such as depression2</li><li>The estimated number of people living with anxiety disorders in the world is 264 million with South-East Asia Region making up 23% and the Western Pacific Region making up 20% of the global total3 </li><li>Anxiety is more common amongst females than males (4.6% compared to 2.6% globally)3</li></ul> </li></ul> </li></ul>

<h2>Management principles</h2><ul><li>Provide or refer for psychoeducation (education about the nature of anxiety, its purpose and presentation)2</li><li>Refer for psychological treatments2 including: <ul><li>Psychologist referral and/or online resource for assessment/treatment2,4</li><li>Cognitive behavioural therapy (CBT) may be at least as effective as medication for many anxiety disorders.2 Patients tend to prefer CBT and see it as more likely to be effective in the long term2</li><li>Online programs may be as effective as face-to-face therapy4</li><li>Mindfulness-based meditation may decrease anxiety with benefits still present after 3 years5</li></ul> </li><li>Consider the patient’s current prescriptions of pharmacological treatments: selective serotonin reuptake inhibitors (SSRIs), serotonin noradrenaline reuptake inhibitors (SNRIs) and benzodiazepines </li><li>Consider diet and lifestyle influences such as the influence of caffeine, nicotine and alcohol, the amount of physical activity and quality of sleep</li><li>Recommend evidence-based nutritional and herbal supplements where appropriate</li></ul>

Management

<h2>Primary recommendations</h2><h2>VITAMIN B COMPLEX</h2>Mechanism of action<ul><li>Folate, B6 and B12 have a role in neural health and energy metabolism.6 They are also involved in the metabolism of the potentially toxic amino acid homocysteine (Hcy) to methionine. High Hcy and low B vitamins may be associated with poorer cognitive function and neurodegenerative disorders.6,7 Chronic stress depletes B66</li><li>Several B vitamins are integral to the synthesis of neurotransmitters and catecholamines that are essential for psychological wellbeing, including serotonin and dopamine7,8 </li></ul>Research<ul><li>2 double-blind randomised controlled trials (RCTs) assessing effects of B complex-containing multivitamins on mood, psychological strain and cognitive effects7,8 reported: <ul><li>Significantly reduced personal strain, confusion and dejected / depressed moods associated with chronic work stress after 12 weeks of supplementation8</li><li>Significant improvements in scales of mood and stress states and performance trend toward reduced mental fatigue during intense mental processing7</li></ul> </li><li>A meta-analysis (8 trials) found that multivitamin / mineral supplementation for at least 28 days reduced levels of perceived stress, mild psychiatric symptoms, and anxiety, and that supplements containing high doses of B vitamins may be more effective in improving mood states9</li></ul>Dosage<table> <tr><th>B Vitamin</th><th>Adult RDIs10</th><th>Adult treatment levels for vitamin B complex used in occupational stress study8</th></tr> <tr><td>B1 (thiamine)</td><td>1.1-1.6 mg/day</td><td>75 mg/day</td></tr> <tr><td>B2 (riboflavin)</td><td>1.1 – 1.2 mg/day </td><td> 10 mg/day </td></tr> <tr><td>B3 (nicotinamide)</td><td>14-16 mg/day </td><td> 100 mg/day </td></tr> <tr><td>B5 (pantothenic acid) </td><td>4-5 mg/day </td><td> 68.7 mg/day </td></tr> <tr><td>B6 (pyridoxine hydrochloride) </td><td>1.3 – 1.7 mg/day </td><td> 25 mg/day </td></tr> <tr><td>B9 (folate/folic acid) </td><td>400 mcg/day </td><td> 150 mcg/day </td></tr> <tr><td>B12 (cyanocobalamin) </td><td>2.4 mg/day </td><td> 30 mcg/day </td></tr> <tr><td>Choline </td><td>425-550 mg/day </td><td> 25 mg/day </td></tr> </table>Adverse effects<ul><li>High doses of vitamin B6 taken over a long period of time may cause peripheral neuropathy.11 This is unlikely to occur at doses &lt;200 mg/d 12</li></ul>Key interactions<ul><li>Vitamin B6 may decrease blood levels of phenytoin and phenobarbitone. Monitor for drug effectiveness and exercise caution when these drugs are being taken concurrently</li><li>Folic acid may decrease the activity of phenytoin and methotrexate. Folic acid may increase the toxicity of fluorouracil. Use with caution under supervision of a HCP13</li><li>Long term use of antibiotics (including aureomycin, erythromycin, streptomycin), oral contraceptives and loop diuretics increases risk of vitamin B complex deficiency13</li></ul><h2>ASHWAGANDHA (Withania somnifera)</h2>Mechanism of action<ul><li>Adaptogenic (Anti-stress) – significant attenuation of high blood cortisol and other physiological indicators of stress and the anti-stress potential of the active constituents sitoindoside VII and VIII has been established in vivo14,15 It has been hypothesised that this normalisation of chronically-increased cortisol/corticosterone in the blood and saliva is due to the direct interaction with glucocorticoid receptors in the brain16</li><li>Anxiolytic – glycowithanolides exert anxiolytic effects in vivo17</li><li>Cognitive - reduces damage to hippocampal neurons by 80% and Withanolide A has been found to reverse the memory deficits and induce regeneration of dendritic spines and axonsin vivo14</li><li>Sedative - GABAergic activity on ionotropic GABA-A and GABA-ρ receptors shown in the treatment of insomnia14 </li></ul>Research<ul><li>A 2012 prospective, randomised double-blind, placebocontrolled study of safety and efficacy of a highconcentration full-spectrum extract of Ashwagandha root in reducing stress and anxiety in 64 adults.15 The extract KSM-66 is standardised to withanolide content of at least 5% and the treatment group received a capsule of KSM-66 extract daily.15 The treatment group exhibited a significant reduction (P&lt;0.0001) in scores on all the stress-assessment scales on day 60 relative to the placebo group.15 The serum cortisol levels were substantially reduced (P=0.0006) in the Ashwagandha group compared to placebo group15</li><li>A 2017 randomised, placebo-controlled trial of body weight management in adults (n=52) under chronic stress treated with Ashwagandha root extract (KSM-66) found those in the treatment group had improvements of primary efficacy measures (e.g. Perceived Stress Scale) and secondary efficacy measures (e.g. Oxford Happiness Questionnaire, serum cortisol, body weight and body mass index)14</li></ul>Dosage informationDried root: 3-6g in capsule17 Adverse effectsAshwagandha extract is well-tolerated and adverse effects comparable to placebo.14,15Key interactions<ul><li>Chemotherapeutic agents (doxorubicin, cyclophosphamide, epirubicin, fluorouracil): may improve chemotherapy-induced fatigue (human study Ashwagandha 6 g/day throughout 6 months chemotherapy in breast cancer patients). Likelihood possible, severity of outcome low with HCP intervention being unlikely to be required. Recommendation is to use with caution under supervision of a HCP13</li><li>Psychotrophic drugs (olanzapine, typical anti-psychotics, antidepressants, mood stabilisers, antianxiety and hypnotic): may improve negative, general and total symptoms and stress by improving neurotransmitter dysfunctions due to GABAergic and NMDA potentiating activity of ashwagandha. Clinical trials showed that ashwagandha as an adjunctive treatment with extract of ashwagandha 1000 mg daily improved negative symptoms of stress in patients with recent exacerbation of schizophrenia. Another clinical trial showed extract of ashwagandha 500 mg/d improved cognitive abilities without serious adverse effects. Possible likelihood of interaction, with a low severity of outcome and with the recommendation to use with caution under supervision of HCP13</li></ul><h2>KAVA (Piper methysticum)</h2>Mechanism of actionKava’s key active constituents, the kavalactones, may:<ul><li>Modulate calcium and sodium channels18,19 </li><li>Modify binding of ligands to GABA receptors18,19 </li><li>Inhibit noradrenaline and dopamine reuptake18,19 </li><li>Reverse inhibition of monoamine oxidase18,19 </li></ul>Research<ul><li>A 2003 Cochrane review (12 RCTS; n=700) found kava extract had a significant effect in reducing anxiety scores and is an effective symptomatic treatment for anxiety20</li><li>A 2005 meta-analysis (6 RCTs; n=345) found kava extract was effective in patients with nonpsychotic anxiety disorders21</li><li>A 2013 RCT (n=75) found an aqueous extract of kava (120/240 mg/d kavalactones) significantly reduced anxiety in patients with GAD. With patients with moderate-severe GAD, the effect size was larger22</li><li>There is contradictory evidence for kava being comparable to pharmaceutical antianxiety agents. One clinical trial found kava was as effective as buspirone in the acute treatment of out-patients suffering from GAD.23 Another trial compared effects of kava and oxazepam on anxiety after a cognitive battery. Kava did not reduce anxiety compared to oxazepam, however, it did not affect cognition whereas oxazepam reduced alertness. The placebo group had an increase in anxiety24</li><li>A randomised controlled trial comparing kava, oxazepam and placebo found a medicinal dose of kava containing 180 mg of kavalactones did not impair driving ability, whereas 30 mg of oxazepam caused some impairment25</li></ul>Adverse effects<ul><li>Well tolerated short term (1–24 weeks).20 May cause GI upset and headache11</li><li>Kava has been implicated in several idiosyncratic, rare cases of liver damage. Aqueous extracts are likely to be safer in this context26</li><li>Not recommended during pregnancy and lactation26</li></ul>Key interactions<ul><li>Concomitant use with alcohol, barbiturates, benzodiazepines, or other CNS depressants may increase risk of drowsiness and motor reflex depression11</li></ul> For more information on key interactions visit: <a href="~/link.aspx?_id=4471DACF65C148EA8FD82B23FD6712D4&_z=z">https://www.blackmoresinstitute.org/interactions</a>

Primary

<h2>Seconday recommendations</h2><h2>MAGNESIUM (Mg)</h2>Mechanism of action<ul><li>Mg status is associated with subjective anxiety, leading to proposition that Mg supplementation may attenuate anxiety27 </li></ul>Research<ul><li>A systematic review including 18 studies recruited samples based on vulnerability of anxiety: mildly anxious, premenstrual syndrome (PMS), postpartum status and hypertension. Four out of eight studies in anxious samples, four out of seven studies in PMS samples, and one out of two studies in hypertensive samples reported positive effects of Mg on subjective anxiety states. No effect on postpartum anxiety. Overall suggestive of a beneficial effect of Mg on subjective anxiety in anxiety-vulnerable samples, however noted well-designed RCTs are required to further confirm the efficacy of Mg supplementation27</li></ul>Dosage Adults: 350 mg/day elemental Mg28 Adverse effectsHypermagnesaemia is rare and is seen mostly in the elderly with renal insufficiency.The most common adverse effect of oral supplementation is diarrhoea. Divide doses to reduce risk and maximise bioavailability.11Key interactions<ul><li>Amphotericin-B: may decrease blood levels of nutrient. Assess nutrient status and supplement if indicated13</li><li>Antiarrhythmic drugs: Mg may have additive antiarrhythmic effect. Use with caution under supervision of a HCP and monitor13</li><li>Anticoagulant and antiplatelet agents: Mg may reduce the efficacy of warfarin. Avoid concomitant use13</li><li>Antihypertensive drugs (calcium channel blockers): Mg may have additive hypotensive effect. Use with caution under supervision of a HCP and monitor13</li><li>Biphosphonates: may form complexes with multivalent cations such as Mg. Avoid concomitant use13</li><li>Digoxin, chlorpromazine, penicillamine, tetracycline, nitrofurantoin and quinolone antibiotics: may decrease drug effect, separate medication and Mg by at least 2 hours13</li><li>Gabapentin: may decrease drug effect. Avoid concomitant use13</li><li>Loop and thiazide diuretics: may decrease blood levels of nutrient. Assess nutrient status and supplement if indicated13</li><li>Proton pump inhibitors: PPIs may cause hypomagnesaemia if taken long-term (usually &gt;1 year). Assess nutrient status and supplement if indicated13</li><li>Proguanil: may decrease drug effect. Avoid concomitant use13</li><li>Rocuronium: may have additive inhibitory effects on acetylcholine release. Use with caution under supervision of a HCP and monito13</li></ul><h2>FISH OIL (omega-3)</h2>Mechanism of action<ul><li>Improve the neuronal membrane structure28 </li><li>Involved in endocrine and immune functions28 </li></ul>Research<ul><li>Several clinical studies show beneficial effects of omega-3 fatty acids including improved mood profile, increased vigour, and reduced anger, anxiety and depression states28 </li><li>Study of male college students (n=126) showed that administration of a polyunsaturated fatty acid mixture of omega-3 and omega-6 (ratio: 1:4) in n=88 (n=38 received placebo) improves the behavioural variables associated with test anxiety symptoms, i.e. appetite, mood, mental concentration, fatigue, academic organisation and poor sleep, as well as lowering elevated cortisol level, with a corresponding reduction of anxiety29 </li><li>Non-depressed patients with social anxiety disorder (n=27) compared with placebo (n=22) found those with seasonal affective disorder (SAD) had lower erythrocyte concentrations28 </li><li>Double-blind, randomised placebo-controlled trial in substance abusers (n=24) found that after supplementation with 3g of omega-3 for 3 months, their anxiety was significantly improved (p=0.001) and this was sustained for 6 months after the end of intervention (p=0.042)28 </li><li>Further research is still needed, and inconsistencies do exist amongst the research28 </li></ul>DosageAdults: 1g 1-3 times daily28 Children: 500 mg 1-2 times daily28 Adverse effectsUp to 3 g/d EPA+DHA is generally recognised as safe (GRAS)13 Key interactions<ul><li>Antihypertensive drugs: may have an additive hypotensive effect depending on fish oil dose. BP should be monitored when patient is on high-dose fish oil13</li><li>Anticoagulant and antiplatelet agents: high doses of fish oil (&gt;3 g/day omega-3 fatty acids) may increase the risk of bleeding with these drugs. There is conflicting data: multiple clinical trials have found no increase in risk of bleeding with antiplatelet or anticoagulant drugs, however there are some studies that suggest an interaction, particularly at higher doses. Use with caution under supervision of a HCP and monitor13</li><li>Chemotherapeutic agents: may decrease drug effect. Avoid concomitant use13</li></ul><h2>OTHER HERBAL MEDICINES FOR STRESS AND ANXIETY</h2><ul><li>St. John’s wort (Hypericum perforatum) has high level evidence for mild to moderate severe depression, and as anxiety is often a symptom of depression, it may be helpful with anxiety symptoms. Case reports support this28</li><li>Valerian (Valeriana officinalis) has both a hypnotic and anxiolytic action11 and is frequently used for people experiencing difficulty getting to sleep. Acute administration of valerian is shown to reduce anxiety in women undergoing gynaecological procedures30 and young adults undergoing dental surgery.31 Further research into valerian’s anxiolytic action is needed</li><li>Passionflower (Passiflora incarnata) preliminary evidence suggests that passionflower may modulate the GABA system and bind to central benzodiazepine receptors, 32,33 supporting its traditional use as a mild sedative and for anxiety33</li><li>Sage (Salvia officinalis) a double-blind, placebo, cross-over study of 30 healthy participants aimed to assess the effect of sage on mnemonic performance and mood. Participants were randomised to placebo, 300-600 mg/day of dried sage leaf and assessed every 7 days on 3 occasions. Both doses of sage led to improved ratings of mood, with the lower dose improving anxiety and the higher dose increasing alertness, calmness and contentedness compared with placebo28</li></ul> For more information on key interactions visit: <a href="~/link.aspx?_id=4471DACF65C148EA8FD82B23FD6712D4&_z=z">https://www.blackmoresinstitute.org/interactions</a>

Secondary

<h2>Diet and lifestyle</h2><ul><li>Adopt a diet rich in complex carbohydrates, (wholegrains, fruits, vegetables), lean protein and omega-3 rich foods. Decrease refined carbohydrates, saturated fats, and processed foods18</li><li>Exercise therapy (moderate-graded physical activity) may decrease the risk of anxiety18</li><li> Encourage reduction of alcohol, caffeine and nicotine which may exacerbate18</li><li>Mindfulness and other forms of meditation may reduce anxiety and stress-related symptoms18</li><li>Naturopathic medicine, acupuncture, yoga and Tai chi have tentative supportive evidence18</li></ul>

Diet & lifestyle

<h2>References</h2>1. Kyrios M et al. Anxiety disorders. Assessment and management in clinical practice. Aus Fam Phys 2011; 40(6):370-74.2. Mayo-Wilson E et al. Media-delivered cognitive behavioural therapy and behavioural therapy (self-help) for anxiety disorders in adults. Cochrane Database of Systematic Reviews 2013; (9):CD005330.3. World Health Organization. Depression and Other Common Mental Disorders. Global Health Estimates 2017 https://apps.who.int/iris/bitstream/ handle/10665/254610/WHO-MSD-MER-2017.2-eng.pdf.4. Reynolds J et al. Anxiety and depression. Online resources and management tools. Aus Fam Phys 2011; 40(6):382-86.5. Allen NB et al. Mindfulness-based psychotherapies: a review of conceptual foundations, empirical evidence and practical considerations. Aust NZ J Psch 2006: 40(4):285-94.6. Stough C et al. Reducing occupational stress with a B-vitamin focussed intervention: a randomized clinical trial: study protocol. Nutr J 2014; 13(1):122.7. Kennedy D et al. Effects of high-dose B vitamin complex with vitamin C and minerals on subjective mood and performance in healthy males. Psychopharmacol 2010; 211(1):55-68.8. Stough C et al. The effect of 90-day administration of high dose vitamin B-complex on work stress. Hum Psychopharmacol 2011; 26(7):470-6.9. Long S et al. Effects of vitamin and mineral supplementation on stress, mild psychiatric symptoms and mood in nonclinical samples: a meta-analysis. Psychosom Med 2013; 75(2):144-53.10. Australian Government. NHMRC. Nutrient Reference Values for Australia and New Zealand. https://www.nrv.gov.au/11. Braun L, Cohen M. Herbs &amp; Natural Supplements. 3rd ed. Chatswood: Elsevier; 2010.12. Higdon J. An evidence-based approach to vitamins and minerals. Thieme, New York. 2007.13. Blackmores Institute. Complementary Medicine Interaction Guide. https://www.blackmoresinstitute.org/interactions14. Choudhary D et al. Body weight management in adults under chronic stress through treatment with Ashwagandha root extract: a double-blind randomised, placebo-controlled trial. J Evid Based Complementary Altern Med, 2017, Vol. 22(1) 96-106.15. Chandrasekhar K et al. A prospective, randomized double-blind, placebo-controlled study of safety and efficacy of a high-concentration full spectrum extract of Ashwagandha root in reducing stress and anxiety in adults. India J Psychol Med. 2012 Jul-Sep; 34(3):255-262.16. Panossian A. Understanding adpatogenic activity: specificity of the pharmacological action of adaptogens and other phytochemicals. Ann. N.Y. Acad. Sci. ISSN 0077-892317. Braun L, Cohen M. Withania. Herbs &amp; Natural Supplements. An evidence-based guide Elsevier. 4th edition 2015 Volume 2, 118518. Sarris J et al. Complementary medicine, exercise, meditation, diet, and lifestyle modification for anxiety disorders: a review of current evidence. Evid Based Complement Alternat Med 2012; 2012:809653.19. Lakhan SE et al. Nutritional and herbal supplements for anxiety and anxiety-related disorders: systematic review. Nutr J 2010; 9:4220. Pittler MH et al. Kava extract for treating anxiety. Cochrane Database Syst Rev 2003; (1):CD00338321. Witte S et al. meta-analysis of the efficacy of acetonic kava extract WS®1490 in patients with non-psychotic anxiety disorders. Phytother Res 2005;19:183-8822. Sarris J et al. Kava in the treatment of generalised anxiety disorder: a double-blind, randomised, placebo-controlled study. J Clin Psychopharmacol 2013:33(5):643-823. Boerner R J et al. Kava-Kava extract LI 150 is as effective as opipramol and buspirone in generalised anxiety disorder: an 8-week randomized, doubleblind multi-centre clinical trial in 129 out-patients. Phytomedicine 2003; 10 (Suppl 4):38-4924. Sarris J et al. The acute effects of kava and oxazepam on anxiety, mood, neurocognition; and genetic correlates: a randomized, placebo-controlled, double- blind study. Hum Psychopharmacol 2012; 27(3):262-9.25. Sarris J et al. Does a medicinal dose of kava impair driving? A randomized, placebo-controlled, double-blind study. Traffic Inj Prev. 2013;14(1):13-726. Bone K, Mills S. Principles and Practice of Phytotherapy 2nd ed. Elsevier 201327. Boyle NB. The Effects of Magnesium Supplementation on Subjective Anxiety and Stress-A Systematic Review. Nutrients. Apr 26:9(5) 201728. Kotsirilos V et al. A guide to evidence-based integrative and complementary medicine. Elsevier Australia. 2011, 68-8729. Yehuda S et al. Mixture of essential fatty acids lowers test anxiety. Nutr Neurosci. Aug;8(4):256-730. Gharib M et al. The effect of valeric on anxiety severity in women undergoing hysterosalpingography. Global Journal of Health Science 2015;7(3):358-63.31. Pinheiro M L et al. Valeriana officinalis L. for conscious sedation of patients submitted to impacted lower third molar surgery: A randomised, double-blind, placebo-controlled split-mouth study. Journal of pharmacy &amp; bioallied sciences 2014;6(2):109-1432. Elsas SM et al. Passiflora incarnata L. (Passionflower) extracts elicit GABA currents in hippocampal neurons in vitro, and show anxiogenic and anticonvulsant effects in vivo, varying with extraction method. Phytomedicine 2010; 17(12):940-9.33. Ulbricht C, Basch E, Boon H, et al. An evidence- based systematic review of passion flower (Passiflora incarnata L.) by the Natural Standard Research Collaboration. J Diet Suppl 2008; 5(3):310-40.

Stress and mild anxiety

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