Chronic stress and anxiety are recognised as contributors to the pathogenesis of a range of chronic diseases and can lead to decreased quality of life. It is estimated that 75-90% of visits to primary care physicians are due to acute or chronic stress. Chronic stress may suppress both cellular and humoral immunity, which can exacerbate allergy and many kinds of autoimmune disease.
Levels of stress among Australians appear to be increasing, with younger adults reporting the highest levels of stress. The National Survey of Mental Health and Wellbeing found almost half of Australian adults met the criteria for the diagnosis of a mental health disorder at some stage of their lives. Of these mental health disorders, anxiety disorders were the most common, affecting over 14% of adults in the 12 months prior to the survey, with women more affected than men.[5,6]
Causes of stress and anxiety[4,6]
- Bullying or peer pressure
- Environmental issues
- Family history of mental health
- Health of others
- Health of self
- Issues in the workplace/school
- Major life changes
- Personality type
- Substance abuse
Treatments for stress and anxiety
- B vitamins
- Holy basil
- Lemon balm
- Sour cherry
- St John’s wort
Mechanisms of action
The stress response begins in the brain, with the hypothalamus activating the sympathetic nervous system (SNS). Upon activation, the adrenal glands release adrenaline into the bloodstream causing an increase in heart rate, blood flow, blood pressure, and the release of glucose and fats into the bloodstream – the ‘fight or flight’ response.
The hypothalamic-pituitary-adrenal (HPA) axis is then activated and involves the release of corticotropin-releasing hormone (CRH) which travels to the pituitary gland triggering the release of adrenocorticotropic hormone (ACTH). ACTH travels to the adrenal glands triggering the release of cortisol. In a healthy stress response, a feedback mechanism signals the hypothalamus to stop producing CRH when the stressful situation has passed.
Chronic stress dysregulates the HPA axis and the SNS, decreasing their activity and contributing to many disease states including depression, anxiety, cardiovascular disease, digestive problems, cognitive impairment, upper respiratory tract infections, diabetes, asthma, viral infections, autoimmune disease and impaired wound healing.[7,8-10]
Chronic engagement of the fight or flight mechanism leads to a disruption of the normal circadian release of cortisol and results in elevated cortisol and catecholamine stress hormone levels. Emerging evidence suggests that under chronic stress the body may develop glucocorticoid receptor resistance (GCR), whereby the body fails to down-regulate the chronic stress-induced inflammatory response leading to the onset and progression of inflammatory conditions such as CVD.
Systemically, chronic stress:
- suppresses immune function via impaired natural killer (NK) cell activity and decreased secretory IgA (sIgA) levels
- increases activation of immune-mediated inflammation
- disrupts digestive function by impairing gastrointestinal barrier function  and altering intestinal microflora (decreasing bifidobacterium and lactobacilli and increasing enterobacteria and E. coli)
- impairs cardiovascular function by promoting atherosclerosis, increasing platelet aggregation, increasing arrhythmias, and increasing susceptibility to myocardial ischemia and coronary artery disease.[7,12]
The general adaptation syndrome is outlined in Table 1 and describes the body’s reaction and adaptation to stress. Current research suggests that the pathophysiology of anxiety disorders involves abnormalities of serotonergic, noradrenergic, glutamatergic and gamma-aminobutylic acid (GABA)-ergic transmission.
B vitamins are integral to the health and functioning of the nervous system. They are important cofactors in the biosynthesis of neurotransmitters including GABA, dopamine and serotonin, and are required for adrenal cortex function and steroid hormone synthesis. Table 2 outlines the functions and doses for the B vitamins.
Holy basil (Ocimum tenuiflorum)
Holy basil’s mechanism of action may involve the prevention of brain catecholamine and monoamine oxidase reduction, and promotion of increased dopamine and 5-hydroxytryptamine, according to animal studies.
In humans, supplementation with holy basil has shown to significantly decrease stress related symptoms including forgetfulness, sexual problems, exhaustion and sleep problems, and significantly improve the symptoms of generalised anxiety disorder.[18,19]
Kava (Piper methysticum)
The active constituents of kava interact with dopaminergic, serotonergic, GABA-ergic and glutamatergic neurotransmission, and inhibit monoamine oxidase B.
Kava compares favourably to benzodiazepines in effectiveness for the treatment of anxiety, without the rebound symptoms experienced with abrupt benzodiazepine withdrawal.
Lactium, a bioactive peptide derived from milk protein, shows anxiolytic activity, leading to a reduction in stress-related symptoms and improvement in sleep.[12,20]
Lactium supplementation decreased plasma cortisol concentrations and resulted in smaller changes to blood pressure in subjects facing mental and physical stress situations, compared to placebo.
Lemon balm (Melissa officinalis)
The active constituents of lemon balm bind to GABA-A receptors and increase the affinity of GABA to receptors. Clinical trials utilising lemon balm found it effective for anxiety, improving sleep, increasing calmness and improving cognitive performance.[22-24]
Stress and anxiety may lead to magnesium depletion and impaired magnesium homeostasis through increased urinary excretion and a shifting of intracellular magnesium to the extracellular space.25-28 Magnesium may play a role in HPA axis modulation, with magnesium deficiency associated with increased anxiety.
Magnolia officinalis and Phellodendron amurense
The combination of magnolia and phellodendron has been clinically shown to reduce anxiety, perceived stress and overeating associated with stress.[30,31] Magnolia and phellodendron may exert these benefits by reducing cortisol and enhancing the activity of GABA receptors.[32,33]
Research shows rhodiola to possess neuroprotective, cardioprotective, antifatigue, antidepressant and anxiolytic effects.
Human studies have found rhodiola effective in reducing anxiety, depression and fatigue, while improving mental and physical performance.[17,35,36]
SAMe is found in high concentrations in the liver, adrenal glands and pineal gland. It functions as the major methyl donor in the body and is involved in the methylation of a range of targets including neurotransmitters. A wide body of evidence supports the use of SAMe in mood disorders, in particular depression.
Saffron (Crocus sativus)
Saffron inhibits the reuptake of the monoamines (dopamine, serotonin and noradrenaline) and acts as a GABA agonist.[13,38]
Clinical trials have shown saffron to be superior to placebo and therapeutically similar to prescription antidepressants for the treatment of depression.
Sour cherry (Prunus cerasus)
Sour or tart cherries are rich in phytochemicals including melatonin, a hormone involved in the regulation of the sleep-wake cycle. Sour cherries are also high in anti-inflammatory compounds, which may also account for its efficacy in improving sleep as inflammatory cytokines are intricately related to the modulation of sleep. Clinical studies have demonstrated the effectiveness of sour cherry in improving sleep duration and quality in healthy individuals and those suffering from insomnia.[39,40]
St John’s wort (Hypericum perforatum)
St John’s wort appears to exert its anxiolytic and antidepressant effects via a range of mechanisms including inhibiting the reuptake of neurotransmitters such as serotonin, dopamine, noradrenaline, L-glutamate and GABA. Clinical trials show St John’s wort to be beneficial in the treatment of mild, moderate and severe depression and its related symptoms.
Tyrosine is a precursor for the synthesis of the neurotransmitters dopamine, adrenaline and noradrenaline. By elevating tyrosine concentrations in these catecholamine neurons, neurotransmitter production is enhanced when the neurons are firing at an increased rate due to stress.
Clinical studies show tyrosine is beneficial in reducing stress and fatigue while improving performance, and may also have an antidepressant effect in certain individuals.
Withania (Withania somnifera)
Withania is an adaptogen with demonstrated antistress and cognition-enhancing activity.[42,43] Human and animal studies have shown withania to negate the effects of chronic stress by suppressing stress-induced increases in dopamine receptors, reducing serum cortisol levels and acting as a GABA-mimetic agent by binding to GABA receptors.[15,42]
Dosage range according to clinical studies:
Cautions and contraindications
- The concomitant use of St John’s wort and drugs that increase serotonin levels (tricyclic antidepressants, SSRIs) may result in an additive effect and increase the risk of serotonergic syndrome.
- St John's wort is a potent inducer of several cytochrome P450 (CYP450) enzymes which may lead to increased metabolism and reduced plasma concentrations of many prescription medications.
- Saffron is not recommended in bipolar disorder.
- Theoretically, kava may have an additive effect when used with CNS depressants such as alcohol, barbiturates and benzodiazepines.
- While rare reports of kava and hepatotoxicity exist, it appears that these may be due to the kava extraction process used (methanolic and ethanolic extracts) and other factors including heavy alcohol intake, pre-existing liver disease, genetic polymorphisms of cytochrome P450 enzymes, excessively high doses and co-medication with hepatotoxic drugs.
- Holy basil has antiplatelet effects and may theoretically increase the risk of bleeding when combined with anticoagulant/antiplatelets.
- Lemon balm has sedative qualities and may theoretically cause additive effects when combined with sedative drugs.
- Tyrosine may have additive effects when combined with thyroid hormone medications and antidepressants, and may theoretically exacerbate hyperthyroidism and Graves' disease.[15,17]
- Theoretically, withania may have an additive effect when used concurrently with barbiturates, benzodiazepines, antihypertensive or thyroid medications.[15,17]
- Magnolia may theoretically potentiate the central depressant effects of agents such as alcohol, barbiturates, benzodiazepines and other central nervous system (CNS) depressants.
- Phellodendron is contraindicated in pregnancy due to its berberine content.
- Magnesium may affect the absorption of certain medications including digoxin, anticoagulants, antimalarial drugs, antibiotics (quinolone, tetracycline, aminoglycosides) and bisphosphonates; take at least two hours apart.[49,50]
- Concomitant use of magnesium with calcium channel blockers or anti-arrhythmic medications may potentiate hypotensive or anti-arrhythmic activity.
- Magnesium should be avoided in patients with renal failure or severe renal disease.
- Magnesium is contraindicated in patients with heart block (unless a pacemaker is present).
- Individuals with myasthenia gravis should avoid the use of magnesium supplements.[51,52]
- Avoid SAMe in bipolar disease.[53,54]
- Caution with SAMe use in schizophrenia and Parkinson’s disease.
- Caution with co-administration of SAMe and antidepressants.[15,53]
- SAMe methylates levodopa, which could theoretically reduce the effectiveness of levodopa given for Parkinson’s disease. However this has not been observed clinically.
- Safety has not yet been conclusively established for use of SAMe in pregnancy; possible effects on prolactin levels need to be considered.
- Li AW, Goldsmith CA. The effects of yoga on anxiety and stress. Altern Med Rev 2012;17(1):21-35. [Full Text]
- Head KA, Kelly GS. Nutrients and botanicals for treatment of stress: adrenal fatigue, neurotransmitter imbalance, anxiety, and restless sleep. Altern Med Rev 2009;14(2):114-140. [Full Text]
- Segerstrom SC, Miller GE. Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychol Bull 2004;130(4):601-630. [Full Text]
- Casey L. Stress and wellbeing in Australia survey 2013. Australian Psychological Society: Melbourne, 2013. [Full Text]
- Australian Bureau of Statistics. National survey of mental health and wellbeing: summary of results. Catalogue no. 4326.0. Canberra ACT, 2007. [Link]
- Anxiety. Mind Health Connect, August 2014. Viewed 30 August 2014, www.mindhealthconnect.org.au/anxiety
- Ho RC, Neo LF, Chua AN, et al. Research on psychoneuroimmunology: does stress influence immunity and cause coronary artery disease? Ann Acad Med Singapore 2010;39(3):191-196. [Full Text]
- Cohen S, Janicki-Deverts D, Miller GE. Psychological stress and disease. JAMA 2007;298(14):1685-1687. [Full Text]
- Cohen S, Janicki-Deverts D, Doyle WJ, et al. Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk. Proc Natl Acad Sci 2012;109(16):5995-5999. [Full Text]
- Stress management. Mayo Clinic 2013. Viewed 5 Apr 2014, www.mayoclinic.org/healthy-living/stress-management/in-depth/stress/art-...
- Söderholm JD, Perdue MH. Stress and gastrointestinal tract. II. Stress and intestinal barrier function. Am J Physiol Gastrointest Liver Physiol 2001;280(1):G7-G13. [Full Text]
- Kim JH, Desor D, Kim YT, et al. Efficacy of αs1-casein hydrolysate on stress-related symptoms in women. Eur J Clin Nutr 2007;61(4):536-541. [Full Text]
- Sarris J, Panossian A, Schweitzer I, et al. Herbal medicine for depression, anxiety and insomnia: a review of psychopharmacology and clinical evidence. Eur Neuropsychopharm 2011;21(12):841-860. [Abstract]
- Everly Jnr GS, Lating JM. A clinical guide to the treatment of the human stress response. New York: Springer, 2013.
- Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide, 3rd ed. Sydney: Churchill Livingstone Elsevier, 2010.
- Department of Health and Ageing, National Health and Medical Research Council, Ministry of Health. Nutrient Reference Values for Australia and New Zealand. Commonwealth of Australia, 2006. [Link]
- Natural Medicine Comprehensive Database 2014. Viewed 30 August 2014, www.naturaldatabase.com
- Saxena RC, Singh R, Kumar P, et al. Efficacy of an extract of Ocimum tenuiflorum (OciBest) in the management of general stress: a double-blind, placebo-controlled study. Evid Based Complement Alternat Med 2012;2012:894509. [Full Text]
- Bhattacharyya D, Sur TK, Jana U, et al. Controlled programmed trial of Ocimum sanctum leaf on generalized anxiety disorders. Nepal Med Coll J 2008;10(3):176-179. [Full Text]
- de Saint-Hilaire Z, Messaoudi M, Desor D, et al. Effects of a bovine alpha s1-casein tryptic hydrolysate (CTH) on sleep disorder in Japanese general population. Open Sleep J 2009;2:26-32 [Full Text]
- Messaoudi M, Lefranc-Millot C, Desor D, et al. Effects of a tryptic hydrolysate from bovine milk αs1-casein on hemodynamic responses in healthy human volunteers facing successive mental and physical stress situations. Eur J Nutr 2005;44(2):128-132. [Full Text]
- Kennedy DO, Little W, Scholey AB. Attenuation of laboratory-induced stress in humans after acute administration of Melissa officinalis (lemon balm). Psychosom Med 2004;66(4):607-613. [Abstract]
- Kennedy DO, Wake G, Savelev S. Modulation of mood and cognitive performance following acute administration of single doses of Melissa officinalis (lemon balm) with human CNS nicotinic and muscarinic receptor-binding properties. Neuropsychopharmacology 2003;28(10):1871-1881. [Full Text]
- Cases J, Ibarra A, Feuillère N, et al. Pilot trial of Melissa officinalis L. leaf extract in the treatment of volunteers suffering from mild-to-moderate anxiety disorders and sleep disturbances. Med J Nutrition Metab 2011;4(3):211-218. [Full Text]
- Galland L. Magnesium, stress and neuropsychiatric disorders. Magnes Trace Elem 1991-1992;10(2-4):287-301. [Abstract]
- Werbach MR. Nutritional strategies for treating chronic fatigue syndrome. Altern Med Rev 2000;5(2):93-108. [Full Text]
- Grases G, Pérez-Castelló JA, Sanchis P, et al. Anxiety and stress among science students. Study of calcium and magnesium alterations. Magnes Res 2006;19(2):102-106. [Abstract]
- Cernak I, Savic V, Kotur J, et al. Alterations in magnesium and oxidative status during chronic emotional stress. Magnes Res 2000;13(1):29-36.
- Sartori SB, Whittle N, Hetzenauer A, et al. Magnesium deficiency induces anxiety and HPA axis dysregulation: modulation by therapeutic drug treatment. Neuropharmacology 2012;62(1):304-312. [Full Text]
- Garrison R, Chambliss WG. Effect of a proprietary magnolia and phellodendron extract on weight management: a pilot, double-blind, placebo-controlled clinical trial. Altern Ther Health Med 2006;12(1):50-54. [Abstract]
- Kalman DS, Feldman S, Feldman R, et al. Effect of a proprietary magnolia and phellodendron extract on stress levels in healthy women: a pilot, double-blind, placebo-controlled clinical trial. Nutr J 2008;7:11. [Full Text]
- Alexeev M, Grosenbaugh DK, Mott DD, et al. The natural products magnolol and honokiol are positive allosteric modulators of both synaptic and extra-synaptic GABA(A) receptors. Neuropharmacology 2012;62(8):2507-2514. [Full Text]
- Talbott SM, Talbott JA, Pugh M. Effect of Magnolia officinalis and Phellodendron amurense (Relora®) on cortisol and psychological mood state in moderately stressed subjects. J Int Soc Sports Nutr 2013;10(1):37. [Full Text]
- Panossian A, Wikman G, Sarris J. Rosenroot (Rhodiola rosea): traditional use, chemical composition, pharmacology and clinical efficacy. Phytomedicine 2010;17(7):481-493. [Abstract]
- Darbinyan V, Aslanyan G, Amroyan E, et al. Clinical trial of Rhodiola rosea L. extract SHR-5 in the treatment of mild to moderate depression. Nord J Psychiatry 2007;61(5):343-348. [Full Text]
- Qureshi NA, Al-Bedah AM. Mood disorders and complementary and alternative medicine: a literature review. Neuropsychiatr Dis Treat 2013;9:639-658. [Full Text]
- Papakostas GI, Cassiello CF, Iovieno N. Folates and S-adenosylmethionine for major depressive disorder. Can J Psychiatry 2012;57(7):406-413. [Abstract]
- Akhondzadeh S, Fallah-Pour H, Afkham K, et al. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression: a pilot double-blind randomized trial. BMC Complement Altern Med 2004;4:12. [Full Text]
- Pigeon WR, Carr M, Gorman C, et al. Effects of a tart cherry juice beverage on the sleep of older adults with insomnia: a pilot study. J Med Food 2010;13(3):579-583. [Full Text]
- Howatson G, Bell PG, Tallent J, et al. Effect of tart cherry juice (Prunus cerasus) on melatonin levels and enhanced sleep quality. Eur J Nutr 2012;51(8):909-916. [Abstract]
- Carpenter DJ. St. John's wort and S-adenosyl methionine as "natural" alternatives to conventional antidepressants in the era of the suicidality boxed warning: what is the evidence for clinically relevant benefit? Altern Med Rev 2011;16(1):17-39. [Full Text]
- Chandrasekhar K, Kapoor J, Anishetty S. 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. Indian J Psychol Med 2012;34(3):255-262. [Full Text]
- Pingali U, Pilli R, Fatima N. Effect of standardized aqueous extract of Withania somnifera on tests of cognitive and psychomotor performance in healthy human participants. Pharmacognosy Res 2014;6(1):12-18. [Full Text]
- Lewis JE, Tiozzo E, Melillo AB, et al. The effect of methylated vitamin B complex on depressive and anxiety symptoms and quality of life in adults with depression. ISRN Psychiatry 2013;2013: 621453. [Full Text]
- Stough C, Scholey A, Lloyd J, et al. The effect of 90 day administration of a high dose vitamin B-complex on work stress. Hum Psychopharmacol Clin Exp 2011;26:470-476. [Abstract]
- Sarris J, Kavanagh DJ, Byrne G, et al. The kava anxiety depression spectrum study (KADSS): a randomized, placebo-controlled crossover trial using an aqueous extract of Piper methysticum. Psychopharmacology (Berl) 2009;205(3):399-407. [Abstract]
- Hung SK, Perry R, Ernst E. The effectiveness and efficacy of Rhodiola rosea L.: a systematic review of randomized clinical trials. Phytomedicine 2011;18(4):235-244. [Abstract]
- Akhondzadeh S, Tahmacebi-Pour N, Noorbala AA, et al. Crocus sativus L. in the treatment of mild to moderate depression: a double-blind, randomized and placebo- controlled trial. Phytother Res 2005;19(2):148-151. [Abstract]
- Higdon J. Magnesium. Micronutrient information center, Linus Pauling Institute 2003. Viewed 26 Mar 2014, http://lpi.oregonstate.edu/infocenter/minerals/magnesium/
- Aydin H, Deyneli O, Yavuz D, et al. Short-term oral magnesium supplementation suppresses bone turnover in postmenopausal osteoporotic women. Biol Trace Elem Res 2010;133(2):136-143.
- Kaeser HE. Drug-induced myasthenic syndromes. Acta Neurol Scand Suppl 1984;100:39-47. [Abstract]
- Bashuk RG, Krendel DA. Myasthenia gravis presenting as weakness after magnesium administration. Muscle Nerve 1990;13(8):708-712. [Abstract]
- Papakostas GI, Mischoulon D, Shyu I, et al. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry 2010;167(8):942-948. [Full Text]
- Gören JL, Stoll AL, Damico KE, et al. Bioavailability and lack of toxicity of S-adenosyl-L-methionine (SAMe) in humans. Pharmacotherapy 2004;24(11):1501-1507. [Abstract]