Background
Methods
Literature search and eligibility criteria
Study selection
Data extraction
Quality assessment
Statistical analysis
Results
Function or process | Effects | Suggested mechanisms | Type of evidence (references) |
---|---|---|---|
Cancer | Tumour regression; activation of tumour-suppressive signalling network; oncostatic activity; modulation of oestrogen and androgen; immunomodulation or neuroimmunomodulation; cytoskeletal modulation; modulation of water transport; resynchronisation of the intracellular clock network; modulation of cellular redox status; haematopoiesis; reduced cardiotoxicity; enhanced mitochondrial function; anti-oestrogen; epigenetic regulation; radioprotection | Reduction of cellular proliferation; free radical scavenging; inhibition of the uptake of linoleic acid; stimulation of glutathione production (γ-glutamylcysteine synthase and reduced reactants such as hydroxyl radical, hydrogen peroxide, hypochlorous acid, singlet oxygen, the peroxynitrite anion and peroxynitrous acid); blocking cell-cycle progression from the G phase to the S phase and by increasing p53, p21 and p27Kip1 gene and protein expression (via increased expression of E-cadherin and β1-integrin proteins); stimulation of lymphocytes, monocytes, granulocytes, macrophages, T-helpers (Th1 and Th2), T and B lymphocytes and thrombocytes; NK cell activity; platelet generation; enhancement of the production of cytokines IL-1, IL-2, IL-4, IL-6, IL-10, IL-12, IL-24, IFN-γ and TNF-α; co-activation of protein kinase C and protein kinase A, and phospholipase C; inhibition of angiogenesis (via inhibition of endothelin-converting enzyme-1 and insulin-like growth factor 1); cell apoptosis; inhibition of 17β-oestradiol; stimulation of biopterins; microfilament modulation; switching microfilament phenotypes; improving oxidative phosphorylation and increasing ATP generation; reduced electron leakage and mPTP opening; decrease in gonadal steroids; downregulation of the expression of oestrogen α receptors; potentiation of cytostatic anti-oestrogen sensitivity of chemotherapeutic agents; inhibition of DNA methyltransferase; inhibition of telomerase; inhibition of metastasis; mutations in the melatonin receptors (MLT1 and MLT2); alterations of arylalkylamine N-acetyltransferase; reduced thrombocytopenia; inhibition of prostaglandin E2; inactivation of calmodulin | |
Metabolic and cardiovascular disorders | Anti-oxidative; anti-inflammatory; anti-hypertensive; regulation of lipid and glucose metabolism; reduction of nephrotoxicity | Free radical scavenging; inhibition of pro-inflammatory mediator; iNOS/i-mtNOS; optimisation of nNOS/c-mtNOS; reduction of factor 1-α and NF-κB; downregulation of Bcl-2 and activation of p53 and CD95; increase in catalase activity and reduction in thiobarbituric acid reactive substrates; reduction in lipid peroxidation, creatinine, uric acid and blood urea nitrogen levels | |
Gastrointestinal conditions | Anti-oxidative; anti-inflammatory | Free radical scavenging; inhibition of pro-inflammatory cytokines, cell adhesion molecules, NO production, COX-2 expression, NF-κ activation; regulation of macrophage activity | |
Neonatology and paediatrics | Anti-inflammatory; anti-oxidative; sedative | Reduction of pro-inflammatory cytokines (IL-6, IL-8 and TNF-α) and nitrite/nitrate levels; inflammatory-derived activation of phospholipase A2, lipoxygenase and cyclooxygenases; increased glutathione peroxidase activity; reduction of C-reactive protein | |
Neurodegenerative disorders | Protection against neurodegeneration caused by mitochondrial dysfunction and oxidative/nitrosative stress; apoptosis; prevention of vasoconstriction of cerebral arteries | Activations of mitochondrial cell survival pathways; regulation of apoptosis; silencing of the Rip2/Caspase-1 pathway; reduced mitochondrial inducible NO synthase; increased activity of respiratory complexes I, III and IV; increased activity and expression of antioxidant enzymes; high lipophilicity | |
Mental disorders | Anti-inflammatory; anti-nociceptive; anxiolytic; drug detoxification | Regulating cytokine production of immunocompetent cells; reducing adhesion molecules and pro-inflammatory cytokines including IL-6, IL-8 and TNF; modifying serum inflammatory parameters; neutralising free radicals and non-radical oxygen-based reactants | |
Pain syndromes | Anti-nociceptive, antiallodynic and analgesic effects; synchronisation of biological rhythms | Activation of melatoninergic MLT1/MLT2 receptors; release of opioid peptides (β-endorphins); interaction with opioid, γ-aminobutyric acid or N-methyl-daspartate receptors; NO-arginine pathway; antioxidant and anti-inflammatory effect; regulation of endoplasmic reticulum and mitochondrial activity | |
Reproductive functions | Antioxidant, anti-inflammatory, anti-apoptotic, cytoprotective and neuroprotective effects; reduced risk of complications; increased homeostasis; gonadotropin secretion; higher rate of mature oocytes and quality embryos | Activation of melatoninergic MLT1/MLT2 receptors; inhibition of adenyl cyclase activity; forskolin-induced cAMP formation with subsequent reduction in activated protein kinase; alteration of granulosa cell steroidogenesis and folliculogenesis; corpus luteum function; inhibition of prostaglandins, oxytocin, cortisol production and LDL peroxidation; activation of prolactin secretion; free hydroxyl radicals scavenging; prevention against DNA damage; activation of superoxide dismutase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase; inhibition of NO synthase; deferred apoptosis of villous cytotrophoblasts and protection of syncytiotrophoblasts; improved haemodynamics and nutrient transfer at the placental-uterine interface | |
Sleep disorders | Sleep enhancer; shifted circadian rhythms; reduced duration of jet lag | Activation of alpha-2 noradrenergic receptor agonist clonidine; lowered core body temperature; opening of the sleep gate and facilitation of re-entrainment to suprachiasmatic nuclei; potentiation of GABA on GABAA receptors; inactivation of calmodulin | |
Traumatic CNS injury | Attenuation of neural damage; neuroprotective effects; inhibition of necrosis, apoptosis; immunomodulation; protection of nuclear and mitochondrial DNA; anti-oxidative effects | Free radical scavenging (including the hydroxyl radical, hydrogen peroxide, singlet oxygen, NO, peroxynitrite anion and peroxynitrous acid); inhibition of pro-inflammatory cytokines or quinone reductase 2, calcium ion-mediated toxicity, proxidative enzymes NO synthase, lipoxygenase and phospholipase A2; activation of the tumour necrosis factor receptors; increased efficiency of oxidative phosphorylation; reduction of NF-κB or TNF expression; modulation of angiogenesis; stimulation of superoxide dismutase, glutathione peroxidase, glutathione reductase, catalase and glutathione; induction of γ-glutamylcysteine synthetase; activation of glucose-6-phosphate dehydrogenase |
First author (year) [reference] | Health outcome | No of participants included in MA | No of primary studies included in MA | Reported effect size | Random-effects summary effect size (95% CI) | P random | Fixed-effects summary effect size (95% CI) | P fixed | 95% PI | I2 (%) | Estimate of the study with lowest SE in MA (95% CI)1 | Small-study effects/excess statistical significance |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Addiction | ||||||||||||
Wright2 (2015) [36] | Withdrawal symptoms | 244 | 4 | OR | 1.39 (0.42, 4.65) | 0.594 | 1.11 (0.65, 1.90) | 0.694 | 0.01, 277.67 | 75.9 | 1.00 (0.37, 2.67) | No/No |
Cancer | ||||||||||||
Basler (2014) [68] | Risk of breast cancer | 1650 | 5 | RR | 0.82 (0.68, 0.99) | 0.043 | 0.82 (0.71, 0.95) | 0.01 | 0.50, 1.34 | 31.7 | 0.81 (0.64, 1.02) | No/No |
Wang (2012) [31] | 761 | 8 | RR | 1.95 (1.49, 2.54) | 0.0001 | 1.96 (1.50, 2.56) | 0.0001 | 1.40, 2.71 | 0 | 2.25 (1.39, 3.64) | No/No | |
Wang (2012) [31] | 590 | 5 | RR | 1.90 (1.28, 2.83) | 0.0002 | 1.82 (1.49, 2.24) | 0.0001 | 0.56, 6.47 | 61.9 | 1.26 (0.97, 1.65) | No/No | |
Delirium | ||||||||||||
Chen (2015) [35] | Incidence of delirium | 669 | 4 | RR | 0.41 (0.15, 1.13) | 0.084 | 0.73 (0.55, 0.95) | 0.021 | 0.01, 35.8 | 83.8 | 1.16 (0.83, 1.61) | Yes/No |
Dementia | ||||||||||||
Jansen3 (2009) [30] | Cognition | 121 | 2 | MD | –2.64 (–5.99, 0.71) | 0.123 | –2.12 (–3.82, 0.42) | 0.015 | – | 68.6 | –1.15 (–3.16, 0.86) | –/No |
Jansen (2009) [30] | Mood and behaviour | 150 | 3 | MD | 0.18 (–0.73, 1.10) | 0.698 | 0.18 (–0.73, 1.10) | 0.698 | –5.76, –6.12 | 0 | –0.01 (–1.08, 1.06) | No/No |
Depression/mood disorders | ||||||||||||
De Crescenzo (2017) [127] | Mood disorders | 181 | 3 | SMD | 0.37 (–0.05, 0.78) | 0.087 | 0.39 (0.08, 0.70) | 0.013 | –3.74, 4.47 | 43 | 0.32 (–0.14, 0.78) | No/No |
Guaiana (2013) [34] | Response to treatment | 3826 | 10 | RR | 1.01 (0.95, 1.08) | 0.749 | 1.00 (0.95, 1.06) | 0.881 | 0.87. 1.17 | 31.4 | 1.04 (0.93, 1.15) | No/Yes |
Huang (2014) [65] | 1871 | 6 | RR | 1.07 (1.02, 1.13) | 0.01 | 1.08 (1.03, 1.15) | 0.005 | 0.99, 1.16 | 0 | 1.04 (0.93, 1.15) | No/No | |
Guaiana (2013) [34] | Remission | 3826 | 10 | RR | 0.83 (0.68, 1.02) | 0.069 | 0.87 (0.80, 0.94) | 0.0007 | 0.43, 1.59 | 77.8 | 0.95 (0.85, 1.06) | No/No |
Huang (2014) [65] | 1742 | 5 | RR | 1.11 (1.01, 1.23) | 0.035 | 1.12 (1.01, 1.24) | 0.038 | 0.95, 1.31 | 0 | 1.09 (0.93, 1.27) | No/No | |
Hansen3 (2014) [65] | Hospital Anxiety and Depression Scale | 74 | 2 | MD | 0.97 (–0.84, 2.78) | 0.293 | 0.93 (–0.42, 2.28) | 0.178 | – | 44 | 0.10 (–1.72, 1.92) | –/No |
Hansen3 (2014) [65] | Beck Depression Inventory | 91 | 2 | MD | –1.09 (–2.60, 0.42) | 0.157 | –1.09 (–2.60, 0.42) | 0.157 | – | 0 | –1.00 (–2.54, 0.54) | –/No |
Infertility | ||||||||||||
Seko (2014) [25] | Pregnancy rate | 680 | 5 | RR | 1.21 (0.98, 1.49) | 0.071 | 1.21 (0.98, 1.50) | 0.071 | 0.86, –1.70 | 0 | 1.13 (0.85, 1.51) | No/No |
Seko (2014) [25] | Oocytes retrieved | 680 | 5 | MD | 0.57 (–0.22, 1.35) | 0.155 | 0.23 (–0.12, 0.8) | 0.2 | –1.91, –3.04 | 68.7 | –0.07 (–0.57, 0.43) | Yes/No |
Pre- and post-operative care | ||||||||||||
Andersen (2014) [33] | Pre-operative anxiety | 761 | 11 | SMD | –0.88 (–1.33, –0.44) | <0.0001 | –0.91 (–1.07, –0.75) | <0.0001 | –2.53, –0.76 | 86.7 | 0.00 (–0.33, 0.33) | No/No |
Hansen3 (2015) [169] | 122 | 2 | MD | –1.18 (–2.59, 0.23) | 0.1 | –1.18 (–2.59, 0.23) | 0.1 | – | 0 | –1.30 (–2.76, 0.16) | –/No | |
Hansen3 (2015) [169] | Post-operative anxiety | 73 | 2 | MD | –5.31 (–8.78, –1.84) | 0.003 | –5.31 (–8.78, –1.84) | 0.003 | – | 0 | –5.40 (–10.12, –0.68) | –/No |
Andersen (2014) [33] | Post-operative pain | 524 | 8 | SMD | –1.06 (–1.89, –0.24) | 0.012 | –0.12 (–0.30, 0.07) | 0.205 | –3.97, 1.85 | 94.2 | 0.43 (0.09, 0.77) | Yes/No |
Mihara (2015) [41] | Prevention of agitation | 170 | 3 | RR | 0.31 (0.16, 0.60) | <0.0001 | 0.29 (0.15, 0.56) | <0.0001 | 0.00, 23.06 | 0 | 0.40 (0.18, 0.89) | No/Yes |
Safety | ||||||||||||
Liu (2012) [40] | Adverse effects | 2912 | 7 | RR | 1.10 (1.02, 1.20) | 0.009 | 1.11 (1.03, 1.20) | 0.006 | 1.02, 1.20 | 0 | 1.13 (0.97, 1.31) | No/Yes |
Primary sleep disorders | ||||||||||||
Liu3 (2012) [40] | Sleep latency | 405 | 1 (with six subgroups) | MD | –14.26 (–18.54, –9.98) | <0.0001 | –14.26 (–18.54, –9.98) | <0.0001 | –20.32, –8.19 | 0 | –16.70 (–26.82, –6.58) | –/NE |
Kuriyama (2014) [39] | 5781 | 12 | WMD | –4.15 (–6.82, –1.47) | 0.002 | –3.30 (–4.88, –1.71) | <0.0001 | –11.69, 3.39 | 52.2 | –2.40 (–5.28, 0.48) | No/No | |
Liira (2014) [38] | 148 | 5 | MD | –0.15 (–2.48, 2.18) | 0.899 | –0.41 (–2.32, 1.50) | 0.674 | –5.64, 5.34 | 21.6 | –1.10 (–3.83, 1.63) | Yes/No | |
Liira (2014) [38] | 266 | 7 | MD | 24.30 (9.80, 38.80) | 0.001 | 24.30 (9.80, 38.80) | 0.001 | 5.29, 43.32 | 0 | 23.00 (–3.13, 49.13) | No/No | |
Kuriyama (2014) [39] | Sleep quality | 5812 | 13 | SMD | –0.08 (–0.13, –0.03) | 0.003 | –0.08 (–0.13, –0.03) | 0.003 | –0.14, –0.02 | 0 | –0.15 (–0.27, –0.02) | No/No |
Zhang3 (2016) [157] | 18 | 1 | MD | 4.20 (0.92, 7.48) | 0.012 | 4.20 (0.92, 7.48) | 0.012 | – | – | 4.20 (0.92, 7.48) | –/No | |
Animal studies | ||||||||||||
Yang (2016) [32] | Spinal cord injury | 90 | 6 | MD | 1.52 (0.06, 2.98) | 0.041 | 1.29 (0.82, 1.77) | <0.0001 | –3.69, 6.73 | 89 | 0.16 (–0.88, 1.20) | Yes/No |
First author (year) [reference] | Health outcome | No of participants included in MA | No of primary studies included in MA | Reported effect size | Random-effects summary effect size (95% CI) | P random | Fixed-effects summary effect size (95% CI) | P fixed | 95% PI | I2 (%) | Estimate of the study with lowest SE in MA (95% CI)1 | Small-study effects/excess statistical significance |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Cancer | ||||||||||||
Yang (2014) [70] | Risk of breast cancer | 4550 | 5 | RR | 0.86 (0.78, 0.95) | – | – | – | – | 46.4 | – | – |
Mills (2005) [68] | Risk of death at 1 year | 643 | 10 | RR | 0.66 (0.59, 0.73) | – | – | – | – | 0.0 | 0.64 (0.52, 0.78) | No |
Seely2 (2012) [37] | – | 13 | RR | 0.63 (0.53, 0.74) | <0.001 | – | – | – | 78.0 | |||
Seely2 (2012) [37] | Complete response | – | 12 | RR | 2.33 (1.29, 4.20) | – | – | – | – | – | – | – |
Seely2 (2012) [37] | Partial response/remission | – | 16 | RR | 1.90 (1.43, 2.51) | – | – | – | – | – | – | – |
Seely2 (2012) [37] | Stable disease | – | 12 | RR | 1.51 (1.08, 2.12) | – | – | – | – | – | – | – |
Nocturnal hypertension | ||||||||||||
Grossman (2011) [57] | SBP | 72 | 3 | MD | –6.10 (–10.69, 1.50) | 0.009 | – | – | – | – | –8.00 (–15.02, 0.97) | – |
Grossman (2011) [57] | DBP | 72 | 3 | MD | –3.51 (–6.14, 0.86) | 0.009 | – | – | – | – | –3.90 (–7.68, 0.11) | – |
Primary sleep disorders | ||||||||||||
Braam (2009) [169] | Sleep latency | 170 | 7 | MD | –33.8 (–42.97, –24.70) | p < 0.01 | – | – | – | – | –32.7 (–47.55, –17.85) | – |
Brzezinski (2005) [28] | 177 | 11 | MD | – | – | 4.0 (2.5, 5.4) | – | – | – | – | – | |
Buscemi (2005) [154] | 279 | 14 | WMD | –11.72 (–18.24, –5.20) | 0.0004 | – | – | – | 81.6 | 0.30 (–0.70, 1.30) | – | |
Ferracioli-Oda (2013) [29] | 1468 | 15 | WMD | 10.18 (6.1, 14.27) | <0.001 | 7.06 (4.37, 9.75) | <0.001 | 56.0 | 1.00 (–3.57, 5.57) | – | ||
Van Geijlswijk (2010) [161] | 317 | 9 | MD | –23.27 (–41.72, –4.83) | 0.013 | – | – | – | – | – | – | |
Braam (2009) [169] | Total sleep Time/duration | 183 | 9 | MD | 0.83 (0.57, 1.08) | p < 0.01 | – | – | – | – | 1.09 (0.70, 1.48) | – |
Brzezinski (2005) [28] | 112 | 8 | MD | 12.8 (2.9, 22.8) | – | – | – | – | – | |||
Ferracioli-Oda (2013) [29] | 1016 | 13 | WMD | 8.48 (–4.02, 20.98) | 0.184 | 8.25 (1.75, 14.75) | 0.013 | 44.0 | 7.80 (–0.69, 16.29) | – | ||
Rossignol3 (2011) [143] | – | 5 | Hedge’s g | 1.97 (1.10, 2.84) | <0.001 | – | – | – | – | – | – | |
Van Geijlswijk (2010) [161] | 304 | 9 | MD | –0.67 (–0.89, –0.45) | <0.0001 | – | – | – | – | – | – | |
Braam (2009) [169] | Number of wakes per night | 183 | 9 | MD | –0.16 (–0.30, 0.02) | 0.024 | – | – | – | – | –0.18 (0.35, –0.01) | – |
Brzezinski (2005) [28] | Sleep efficiency | 126 | 7 | MD | – | – | 2.2 (0.2, 4.2) | – | – | – | – | – |
Van Geijlswijk (2010) [161] | Dim-light melatonin onset | 238 | 6 | MD | –1.18 (–1.48, –0.89) | <0.0001 | – | – | – | – | –0.87 (–1.37, –0.37) | – |
Van Geijlswijk (2010) [161] | Wake-up time | 195 | 5 | MD | –0.28 (–0.66, 0.09) | 0.135 | – | – | – | – | –0.20 (–0.45, 0.06) | – |
Secondary sleep disorders | ||||||||||||
Buscemi (2006) [154] | Sleep onset latency | 163 | 6 | MD | –13.22 (–27.33, 0.89) | 0.070 | 2.30 (–0.13, 6.12) | 0.060 | – | 79.2 | 5.8 (2.47, 9.13) | – |
Buscemi (2006) [154] | Sleep restriction | 508 | 9 | MD | –0.97 (–2.26, 0.33) | 0.140 | –0.89 (–1.98, 0.20) | 0.110 | – | 4.0 | –1.05 (2.30, 0.20) | – |
Miscellaneous | ||||||||||||
Marrin (2013) [170] | Core temperature | 193 | 16 | MD | –0.21 (–0.24, –0.18) | <0.001 | – | – | – | – | – | – |
Animal studies | ||||||||||||
Macleod (2004) [27] | Ischaemic stroke | 432 | 13 | ES | 0.43 (0.39, 0.64) | <0.0001 | – | – | – | – | – | – |
Subjects/condition/health outcome/indication | Number of systematic reviews (N) |
---|---|
Ageing | 5 |
Cancer | 43 |
Cardiovascular | 9 |
Delirium | 2 |
Epilepsy | 2 |
Excretory/renal functions | 2 |
Gastrointestinal function/conditions | 7 |
Healthy adults | 6 |
Infections (various) | 6 |
Inflammatory conditions | 10 |
Menopause (symptoms) | 2 |
Musculoskeletal system | 3 |
Neonates, infants and children (various conditions) | 9 |
Nervous system (central and peripheral) conditions/injuries | 18 |
Neurodegenerative disorders/dementias | 10 |
Obesity/metabolic diseases | 10 |
Other (miscellaneous) | 6 |
Oral cavity diseases | 3 |
Pain syndromes | 5 |
Pregnancy/reproductive functions/infertility | 11 |
Pre-operative, peri-operative or post-operative care (anxiety, prevention of agitation) | 4 |
Protection against radiation/metal toxicity | 4 |
Psychiatric/psychological conditions | 22 |
Sleep outcomes/insomnia | 37 |
Various clinical conditions | 10 |