Potential Role of Curcumin for the Treatment of Major Depressive Disorder.

Curcumin is the major biologically active polyphenolic constituent in the turmeric plant (Curcuma longa) that has been shown to have antioxidant, anti-inflammatory, neuroprotective, anticancer, antimicrobial, and cardioprotective effects. Interest in curcumin as a treatment for mental health conditions has increased and there is an expanding body of preclinical and clinical research examining its antidepressant and anxiolytic effects. In this narrative review, human trials investigating the effects of curcumin for the treatment of depression or depressive symptoms are summarised. Using findings from in vitro, animal, and human trials, possible biological mechanisms associated with the antidepressant effects of curcumin are also explored. To increase the understanding of curcumin for the treatment of depression, directions for future research are proposed.

Key Points

Introduction

Curcumin, found primarily in roots and rhizomes of the turmeric plant (Curcuma longa), is the major biologically active polyphenolic constituent in turmeric. In addition to curcumin, other curcuminoids, such as demethoxycurcumin, bisdemethoxycurcumin, and cyclocurcumin, are also found in turmeric, albeit at lower concentrations. Collectively, these curcuminoids make up 2–4% of dry turmeric root powder [1, 2]. Curcuminoids are phenolic compounds commonly used as a spice, pigment, and food additive; however, cell culture and animal studies have demonstrated that curcuminoids, and in particular curcumin, have extensive biological activity, including antioxidant, anti-inflammatory, neuroprotective, anticancer, antimicrobial, and cardioprotective effects [3, 4].

Turmeric has traditionally been used in Indian folk medicine to treat eye infections, skin wounds, respiratory conditions and digestive complaints, and to reduce general inflammation [5, 6]. More recently, interest in curcumin as a treatment for depression has increased and there is an expanding body of research confirming antidepressant and anxiolytic effects from its administration. The aims of this narrative review are to summarise animal and clinical trials examining the antidepressant effects of curcumin and to explore possible mechanisms associated with its antidepressant effects. Directions for future research are also provided to advance the understanding of the use of curcumin for the treatment of depression.

Animal Trials Examining the Antidepressant Effects of Curcumin

A comprehensive summary of animal trials examining the antidepressant and anxiolytic effects of curcumin was published by Lopresti [7]. In brief, animal trials have comprised acute stress exposures such as the forced swimming test, tail suspension test, sleep deprivation, immobilisation-induced restraint stress, and cold-restraint stress. Chronic stress exposure has comprised chronic unpredictable stress models (CUMS), restraint stress for periods ranging from 20 to 56 days, and the acute or chronic administration of anxiety or depressive-inducing exogenous agents such as corticosterone, pentylenetetrazole (γ-aminobutyrate antagonist), reserpine (monoamine antagonist), 4-aminopyridine (potassium channel blocker), lead, mercuric chloride, and lipopolysaccharide (the major component of the outer membrane of Gram-negative bacteria). Surgical procedures such as ovariectomy, bilateral olfactory bulbectomy and ligation of sciatic nerves have also been used to examine the effects of curcumin on stress, depression and anxiety induced by these procedures. A selection of animal studies using the various methods to analyse the antidepressant effects of curcumin is detailed in Table 1. In most of these trials, curcumin was administered orally or via an intraperitoneal injection from 21 days to 30 min before the stressor. When curcumin was administered before the stressor, antidepressant and anxiolytic effects in animals were commonly observed, as measured by changes in behaviour, appetite, socialisation, and weight loss [8-14].

Table 1

A summary of methods used in animal studies to examine the antidepressant effects of curcumin

Exposure to stress-inducing procedures
Chronic restraint stress	[10–12, 15, 23–29]
Forced swimming and/or tail suspension tests	[30–36]
Cold-restraint stress	[37, 38]
Single stress exposure	[20, 39]
Exposure to pain-inducing procedures
Reserpine exposure	[16, 40]
Chronic constriction injury induced by the ligation of sciatic nerves	[19]
Trigeminal neuralgia induced by cobra venom	[41]
Exposure to depression-inducing and neurotoxic agents
Corticosterone	[42–45]
Lipopolysaccharide	[9, 46–48]
Mercury chloride	[8, 49]
Glutamate	[50]
Rotenone	[51]
Tetrabenazine	[52]
Cisplatin	[53]
Pentylenetetrazole	[17]
Amyloid-β peptide	[54]
Exposure to surgical procedures
Ovariectomy	[24, 55]
Olfactory bulbectomy	[56–58]

Surprisingly, there is a lack of animal studies examining the antidepressant and anxiolytic efficacy of curcumin when it is administered after a stressor. Curcumin delivered for 5 weeks after rats were subjected to CUMS for 4 weeks reversed CUMS-induced reductions in sucrose intake and elevations in corticosterone [15]. Curcumin delivered for 2 days after the administration of reserpine (a monoamine antagonist designed to induce pain and depressive behaviour) [16], 15 days after pentylenetetrazole exposure [17], and 14–21 days after surgical procedures to induce anxious or depressive behaviour [18, 19] have also resulted in antidepressant and anxiolytic effects. In animal studies designed to cause post-traumatic stress disorder, the intraperitoneal administration of curcumin for 14 days after stress exposure reduced anxiety-related behaviours in mice [20]. Furthermore, a diet enriched with curcumin consumed either before or after fear conditioning was capable of impairing fear memory consolidation and reconsolidation processes in animals [21]. In the study by Aubry et al. [22], a diet enriched with curcumin delivered 5 days before and during exposure to 10 days of chronic social defeat stress (CSDS) in mice prevented the development of social avoidance, attenuated stress-induced increases in peripheral and central interleukin (IL)-6 and blocked stress-induced increases in hypothalamus-pituitary-adrenal (HPA) axis activity. However, when curcumin was delivered after exposure to CSDS for 3 weeks, it did not reverse the stress-induced behavioural changes in the mice. These results suggest that curcumin may be best delivered before or during stress exposure to have significant effects on depressive or anxious behaviours. These findings could have significant implications on how curcumin is administered in clinical trials and clinical practice, as it is usually administered after the onset of depressive symptoms or stress exposure.

Human Trials Examining the Antidepressant Effects of Curcumin

Studies were identified using the Medline (Pubmed), Cochrane Library, Scopus, Web of Science, and CINAHL databases, and by examining reference lists of relevant papers to locate additional studies that were not identified by the database searches. Databases were scanned from all years of study until October 2021. A systematic search of human trials using the terms (curcumin or turmeric or curcuminoids) and (treatment or trial or intervention or study or clinical) was completed. Specific inclusion criteria for the human trials included the following: (1) published in English; (2) adult human interventional trial (randomised controlled, non-randomised, and open-label) assessing the effects of curcumin or turmeric on depression or affective symptoms; (3) completed pre- and post-intervention outcome measures; and (4) used curcumin or turmeric as a stand-alone or adjunct intervention.

Adults with Depression

As detailed in Table 2, seven trials have examined the effects of curcumin in adults with clinical depression. Treatments lasted 5–12 weeks, with daily dosages ranging from 500 to 1500 mg. Varying curcumin extracts have been utilised in these trials, including non-patented [59-61] and patented extracts such as BCM-95® [62, 63] and C3 Complex® [64]. Curcumin was administered as a stand-alone treatment in three trials [62, 65, 66] and as an adjunct to pharmaceutical antidepressants in four trials [59–61, 63]. Positive antidepressant effects were reported in six of the seven trials, with the only non-significant finding identified by Bergman et al. [59], where curcumin was used as an adjunct to pharmaceutical antidepressants and administered for the shortest treatment period of all the trials (5 weeks). Positive anxiolytic effects from curcumin administration were also identified in four trials [62, 64, 65, 67]. In a recent meta-analysis based on the results from six randomised, double-blind, placebo-controlled trials on people with depression, an effect size of 0.35 compared with placebo administration was identified [68]. Based on the results of a meta-analysis of nine randomised-controlled studies (two on non-depressed populations), a larger effect size of 0.75 compared with placebo was reported by Fusar-Poli and colleagues [69]. Interestingly, in this meta-analysis, an even larger treatment effect was identified when examining the effects of curcumin on anxiety symptoms (Hedge’s g = 2.62). In a meta-analysis conducted in 2016 [70], it was concluded from subgroup analyses that curcumin had the highest antidepressant effects when administered to middle-aged adults, for longer treatment periods, and at higher doses. However, with the addition of more recent publications, these conclusions, along with an exploration of the effects of cultural influences and different curcumin extracts on antidepressant outcomes, will be important.

Table 2

A summary of human clinical trials on the antidepressant effects of curcumin

Study	Population	Design	Treatment	Duration	Measures	Country	Adverse effects	Results
Adults with depression
Bergman et al. (2013) [59]	40 adults with MDD; mean age 64 years; 17 males and 23 females	Randomised, double-blind, placebo-controlled trial	(1) Pharmaceutical antidepressant (escitalopram or venlafaxine) + 500 mg curcumin extract once daily (n = 20); or (2) pharmaceutical antidepressant (escitalopram or venlafaxine) + placebo (n = 20)	5 weeks	CGI, MADRS, HDRS	Israel	No adverse effects reported by participants	No between-group differences in change in outcome measures; however, there was a trend for more rapid improvement in depressive symptoms in the curcumin group
Lopresti et al. (2014) [62]; Lopresti et al. (2014) [79]	56 adults with depression; mean age 46 years; 16 males and 40 females	Randomised, double-blind, placebo-controlled trial	(1) 500 mg curcumin extract (BCM-95®) twice daily; or (2) placebo	8 weeks	IDS-SR30, STAI, various urinary and plasma biomarkers	Australia	No between-group differences in the frequency of adverse effects	From weeks 4–8, curcumin was significantly more effective than the placebo in improving depressive (p = 0.045) and trait anxiety (p = 0.027) symptoms. Larger antidepressant effects were found in people with atypical depression. Curcumin also increased urinary concentrations of thromboxane B2 and substance P; and higher baseline concentrations of endthelin-1 and leptin were associated with greater antidepressants effects from curcumin
Sanmukhani et al. (2014) [63]	60 adults with MDD; mean age 37 years; 21 males and 39 females	Randomised, single-blind trial (observer masked)	(1) Fluoxetine (20 mg) taken in the morning (n = 20); or (2) 500 mg curcumin extract (BCM-95®) twice daily (n = 20); or (3) fluoxetine (20 mg) taken in the morning + 500 mg curcumin extract (BCM-95®) twice daily	6 weeks	HDRS, CGI	India	Increased frequency of gastritis in the fluoxetine + curcumin group	There were no significant between-group differences in changes in outcome measures over time
Panahi et al. (2015 [64]	111 adults with MDD; mean age 41 years; 51 males and 60 females	Open-label	(1) 1000 mg daily of curcumin extract (C3 Complex®), (frequency of dosing not specified) [n = 61]; or (2) placebo	6 weeks	HADS, BDI–II	Iran	Curcumin group: 3 dropouts due to gastrointestinal complications, and 2 due to tachycardia, flushing and gastrointestinal complications	Compared with placebo, curcumin administration significantly reduced the HADS anxiety and depression subscale scores (p < 0.0001) and BDI–II affective, somatic, and cognitive subscale scores (p < 0.0001)
Yu et al. (2015) [60]	108 male adults with MDD; mean age 45 years	Randomised, double-blind, placebo-controlled trial	(1) Escitalopram (5–15 mg daily) + 1000 mg curcumin, daily (frequency of dosing not specified); or (2) escitalopram (5–15 mg daily) + placebo	6 weeks	MADRS, HDRS, plasma BDNF, IL-1β and TNFα, salivary cortisol	China	Reports of mild nausea in the curcumin and escitalopram group	At week 6, compared with placebo, HDRS-17 total score (p < 0.05), MADRS total score (p < 0.05), plasma IL-1β (p < 0.001), TNFα (p < 0.001), and morning salivary cortisol concentrations (p < 0.001) were lower, and plasma BDNF concentrations (p < 0.001) were higher in the curcumin-treated group
Lopresti and Drummond (2017) [65]	123 adults with depression, mean age 43 years, 14 males and 109 females	Randomised, double-blind, placebo-controlled trial	(1) 250 mg curcumin extract (BCM-95®) twice daily (n = 28); or (2) 500 mg curcumin extract (BCM-95®) twice daily (n = 33); or (3) 250 mg curcumin extract (BCM-95®) + saffron extract (Saffron®) twice daily (n = 26); or (4) placebo (n = 36)	8 weeks	IDS-SR30, STAI	Australia	Trend for increased reports of diarrhoea and loose bowels in the high-dose (500 mg twice daily) curcumin group	Compared with placebo, the active treatments were associated with significantly greater reductions in IDS-SR30 (p = 0.031), STAI-state (p < 0.001) and STAI-trait (p < 0.001) scores. There were no differences in efficacy between the active treatment groups
Kanchanatawan et al. (2018) [61]	65 adults with MDD; mean age 44 years; 19 males and 49 females (sex distribution incorrectly cited in the published paper)	Randomised, double-blind, placebo-controlled trial	As an adjunct to pharmaceutical antidepressants with or without psychotherapy: (1) 250 mg curcumin once daily for the first week, then 250 mg twice daily from weeks 1–2, then increasing dose by 250 mg every week until week 4 (reaching a maximum daily dose of 1500 mg daily) [n = 33]; or (2) placebo (n = 32)	12 weeks	MADRS, HAM-A	Thailand	No between-group differences in the frequency of adverse effects	Compared with placebo, curcumin administration significantly decreased the MADRS total score (p = 0.007) but not the HAM-A score. The effects of treatment were greater in males
Non-depressed population
Cox et al. (2014) [71]	60 healthy older-age adults; mean age 68 years; 22 males and 38 females	Randomised, double-blind, placebo-controlled trial	(1) 400 mg curcumin extract (Longvida®) once daily; or (2) placebo	Single dose (acute treatment); and 4 weeks (chronic treatment)	DASS-21, CFS, Bond-Lader Visual Analogue Scales, STAI	Australia	No between-group differences in the frequency of adverse effects and no changes in haematological safety measures	Compared with placebo, chronic curcumin treatment reduced fatigue (p = 0.02) but had no effect on the DASS-21 score (floor effects were observed). After a mental challenge, acute treatment had no effect on mood, but chronic treatment had a positive effect on fatigue, calmness, contentedness and alertness
Esmaily et al. (2015) [72]	30 adults with a BMI ≥ 30 kg/m2; mean age 38 years; 6 males and 24 females	Randomised, double-blind, placebo-controlled, crossover trial	(1) 500 mg twice daily of curcumin extract (C3 Complex®); or (2) placebo (crossover design)	4 weeks	BDI, BAI	Iran	Not reported	Compared with placebo, curcumin had no significant effect on depression but significantly reduced anxiety symptoms (p < 0.05)
Fanaei et al. (2015) [75]	70 women with premenstrual syndrome; mean age 24 years	Randomised, double-blind, placebo-controlled trial	(1) 100 mg curcumin twice daily (n = 35); or (2) placebo (n = 35)	3 consecutive menstrual cycles. Capsules were taken 7 days before and 3 days after onset of menstrual bleeding	PMS symptom self-report questionnaire, serum BDNF	Iran	Not reported	Compared with placebo, there were greater reductions in mood (p < 0.001), physical (p < 0.001), and behavioural (p = 0.005) PMS symptoms. At 3-months after treatment, serum BDNF was higher in the curcumin group compared with the placebo group (p < 0.001)
Asadi et al. (2020) [76]	80 adults with type 2 diabetes; mean age not detailed; 10 males and 70 females	Randomised, double-blind, placebo-controlled trial	(1) 80 mg nano-curcumin capsules once daily (n = 40); or (2) placebo (n = 40)	8 weeks	DASS-21	Iran	Stomach aches reported by 2 participants	Compared with placebo, curcumin administration significantly reduced the DASS-21 depression (p = 0.02) and anxiety score (p = 0.009), but not the stress score (p = 0.6)
Kuszewski et al. (2020) [73]	152 community-dwelling, sedentary adults aged between 50 and 80 years and with a BMI between 25 and 40 kg/m2; mean age 65 years; 69 males and 83 females	Randomised, double-blind, placebo-controlled trial	(1) Fish oil capsules delivering 400 mg EPA and 2000 mg DHA daily (n = 39); or (2) 800 mg curcumin extract (Longvida®) daily (n = 38); or (3) combination of curcumin and fish oil capsules (n = 39); or (4) placebo (n = 36)	16 weeks	POMS, SF-36	Australia	No between-group differences in the frequency of adverse effects	Compared with placebo, curcumin treatment alone significantly improved POMS vigour score (p = 0.044) but had no effect on other POMS subscale scores or SF-36 scores. There were no other significant between-group differences
Latif et al. (2021) [74]	26 young females with a BMI ≥23 kg/m2; mean age 19 years	Single-arm trial	2 g of turmeric in capsules	90 days	DASS-21	Saudi Arabia	No adverse effects were reported by participants	From baseline to post-treatment, there was a significant reduction in the DASS-21 anxiety score (p = 0.03) but not the depression or stress scores
Lopresti et al. (2021) [77]	79 adults with self-reported digestive complaints; mean age 42 years; 10 males and 69 females	Randomised, double-blind, placebo-controlled trial	(1) 500 mg curcumin extract (CurcugenTM) (n = 40) twice daily; or (2) placebo (n = 39)	8 weeks	DASS-21, SF-36	Australia	No between-group differences in the frequency of adverse effects	Compared with placebo, curcumin treatment was associated with a greater reduction in the DASS-21 anxiety score, but there were no other between-group differences in other DASS-21 or SF-36 subscale scores
Ma et al. (2021) [78]	30 adults with pulmonary hypertension; mean age 39 years; 5 males and 25 females	Placebo-controlled trial. Details of randomisation and blinding not disclosed	(1) 60 mg/day of curcumin + conventional antidepressant treatment with the curcumin dose, gradually increasing to 120 mg/day (n = 15); or (2) conventional antidepressant treatment (n = 15)	3 months	SAS, SDS	China	Not reported	At the end of treatment, compared with the placebo group, SAS and SDS scores were significantly lower in the curcumin group (p < 0.05)

BAI Beck Anxiety Inventory, BDI–II Beck Depression Inventory–II, BDNF brain-derived neurotrophic factor, BMI body mass index, CFS Chalder Fatigue Scale, CGI Clinical Global Impression, DASS-21 Depression, Anxiety and Stress Scale–21, DHA docosahexaenoic acid, EPA eicosapentaenoic acid, HDRS Hamilton Depression Rating Scale, HADS Hospital Anxiety and Depression Scale, HAM-A Hamilton Anxiety Rating Scale, IL interleukin, IDS-SR Inventory of Depressive Symptomatology-30, MADRS Montgomery–Asberg Depression Rating Scale, MDD major depressive disorder, PMS premenstrual syndrome, POMS Profile of Mood States, SAS Self-Rating Anxiety Scale, SDS Self-Rating Depression Scale, SF-36 Short-Form-36, STAI State Trait Anxiety Inventory, TNF tumour necrosis factor

Non-Depressed Populations

As detailed in Table 2, the effects of curcumin on mood in non-depressed populations have been investigated in eight trials. This has included an examination into its mood-enhancing effects in healthy, older-age adults [71], overweight or obese adults [72-74], women with premenstrual syndrome [75], adults with type 2 diabetes [76], adults with self-reported digestive complaints [77], and adults with pulmonary hypertension [78]. Treatment dosages ranged from 80 to 2000 mg/day utilising varying curcumin extracts, with treatment periods ranging from a single dose to 4 months. When a change in depressive symptoms was investigated, depressive symptoms were significantly reduced in two of seven trials [76, 78]. Anxiolytic effects were identified in five of seven trials [72, 74, 76–78] that measured changes in anxiety. In a meta-analysis by Wang and colleagues [68], when the antidepressant effects of curcumin were examined in non-depressed populations, an effect size of 0.32 was identified.

Curcumin’s Potential Antidepressant Mechanisms of Action

Depression is associated with a range of biological disturbances that may cause or contribute to its array of behavioural, affective, cognitive and physical symptoms. As detailed in Fig. 1, findings from in vitro, animal and human studies have demonstrated that curcumin has multifactorial physiological effects on the body, which may account for its antidepressant and anxiolytic effects.

Fig. 1

Potential pathophysiological processes in depression restored by curcumin. GI gastrointestinal, BBB blood–brain barrier, HPA hypothalamus-pituitary-adrenal, DHA docosahexaenoic acid

Neurotransmitter Activity

Disturbances in neurotransmitter activity involving serotonin (5-HT), dopamine, noradrenaline [80] and glutamate [81] have been regularly observed in depression. Findings from animal trials have demonstrated curcumin can alter the concentrations and activity of many of these neurotransmitters. For example, the acute administration of curcumin ameliorated depression-like behaviour in mice through its stimulatory influence on the 5-HT1A receptor [30]. In ovariectomised mice, curcumin modulated depression-like behaviours and improved the serotonin content in several brain regions by upregulating tryptophan hydroxylase-2 and 5-HT1A/2A receptor messenger RNA (mRNA) and downregulating monoamine oxidase A mRNA in the limbic system [13]. In rats exposed to single, prolonged stress, curcumin reduced anxiolytic behaviours and restored stress-induced decreases of 5-HT tissue concentrations in the hippocampus, amygdala and striatum [20]. Curcumin has also been shown to modulate dopamine and noradrenaline concentrations in several brain regions in ovariectomised rats [55], reduced diabetes-induced alterations of the dopamine D1 and D2 receptors [82] and ameliorated rotenone-induced dopamine depletion [83]. Rotenone is a commonly used pesticide that causes a depletion of dopamine in the brain [84]. There is also evidence that curcumin can protect against glutamate-induced neurotoxicity by influencing N-methyl-d-aspartate (NMDA) receptor activity by increasing GluN2A subunit expression and facilitating the phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1 [85-88].

Inflammation

A relationship between inflammation and depression is becoming increasingly recognised. Based on several meta-analyses, adults with depression exhibit higher concentrations of proinflammatory markers such as C-reactive protein (CRP), IL-6, and tumour necrosis factor (TNF)-α [89-91]. Moreover, approximately one-quarter of patients with depression show evidence of low-grade inflammation, and over half of patients show mildly elevated CRP levels [91]. Dysregulation in the kynurenine pathway, which is induced by inflammation and in turn fuels inflammation and neurotoxicity, has also been implicated in the pathophysiology of depression [92]. Higher inflammation, demonstrated by elevated concentrations of CRP is also observed in suicidal patients with depression compared with non-suicidal depressed patients [93]. Despite the commonly held belief that pharmaceutical antidepressants target neurotransmitter activity, it is becoming increasingly recognised that they also have anti-inflammatory actions that may at least partly account for their therapeutic activity [94, 95]. In a meta-analysis on antidepressant trials, it was concluded that alterations in peripheral cytokine levels were associated with antidepressant treatment outcomes in major depressive disorder [95].

The anti-inflammatory effects of curcumin have been demonstrated in both animal and human trials. Based on a meta-analysis of 32 human trials, it was confirmed that curcumin lowered concentrations of CRP and high-sensitivity CRP [95]. In another meta-analysis of 15 randomised controlled trials, it was concluded that curcumin supplementation significantly decreased IL-6 and high-sensitivity CRP, but no significant effect on TNF-α was identified [96]. In animal stress and depression models, curcumin administration delivered before CUMS significantly alleviated depression-like behaviours and the expression of the proinflammatory cytokine IL-1β [24]; inhibited cytokine gene expression (TNFα and IL-6) at both the mRNA and the protein level and reduced the activation of Nuclear factor-κB (NF-κB) [97]; and decreased mRNA expression of proinflammatory cytokines IL-1β, IL-6, and TNFα, suppressed NF-κB activation, and inhibited the stressed-induced NLRP3 inflammasome axis activation, along with reducing the transformation of pro-IL-1β into mature IL-1β. The stress-induced activation of indolamine-2, 3-dioxygenase, and an increased kynurenine/tryptophan ratio were also ameliorated by curcumin supplementation [25]. Moreover, lipopolysaccharide exposure in mice induced anxiety and depressive-like behaviours and neurochemical changes in the hippocampus, however pretreatment with curcumin significantly reduced concentrations in the proinflammatory cytokines IL-1β and TNFα [46]. In a placebo-controlled human depression trial, as an adjunct to antidepressants, curcumin decreased inflammatory cytokines IL-1β and TNFα concentrations [60].

Oxidative and Nitrosative Stress

Increased oxidative and nitrosative stress has been regularly identified in depression. This is demonstrated by lower levels of enzymatic and non-enzymatic antioxidants; increased concentrations of oxidative and nitrosative stress markers such as malondialdehyde, protein carbonyls, thiols, and nitrotyrosines; and altered activity of nitric oxide synthase and nitric oxide production [98, 99]. As an antioxidant, curcumin can lower levels of malondialdehyde, protein carbonyls, thiols, and nitrotyrosines; increase the activity of antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase; increase reactive oxygen species and reactive nitrogen species scavenging activity; and protect against the overproduction of nitric oxide [47, 100–102]. In animal stress models, curcumin has protected against increases in oxidative stress by lowing malondialdehyde and protein carbonyl concentrations, and increased the activity of antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase [10, 38, 39, 55]. Human trials have also confirmed curcumin’s antioxidant effects via reductions in malondialdehyde in adults with non-alcoholic fatty liver disease [103] and moderately physically active females [104]. Moreover, increased catalase activity in haemodialysis patients [105] and total antioxidant capacity and glutathione levels in adults with type 2 diabetes and coronary heart disease [106] have been observed. In a meta-analysis based on four studies and 308 participants, it was confirmed that curcumin significantly increased total antioxidant capacity and had a tendency to decrease malondialdehyde concentrations [107].

Hypothalamus-Pituitary-Adrenal Axis Activity

The HPA axis plays a central role in the stress response and, via the release of glucocorticoids (cortisol in humans and corticosterone in rodents), regulates many essential physiological processes. It is estimated that 40–60% of patients with depression experience hypercortisolemia or other HPA-axis disturbances, such as a flattened circadian state rhythm or an earlier or elevated nadir. Elevated HPA axis activity has been identified in depression subtypes such as melancholic depression and depression with psychotic features [108-110]. There have been several animal trials that have confirmed curcumin can lower corticosterone concentrations in mice and rats exposed to various animal stress and depression models. These include after chronic exposure to restraint stress [23], social defeat stress [22], unpredictable mild stress [14], and exposure to mercury chloride [49]. Corticosterone-lowering effects from curcumin may occur via its ability to inhibit adrenocorticotropic hormone secretion [111], its influence on 11β-hydroxysteroid dehydrogenase activity (an enzyme involved in the interconversion of cortisol and cortisone) [112-114] and/or glucocorticoid receptor sensitivity and expression in the brain [26, 115]. In human trials, as an adjunct to antidepressants, curcumin lowered salivary cortisol concentrations compared with placebo [60]; however, in another placebo-controlled trial on adults with depression, it had no significant effect on salivary cortisol concentrations [116]. In a placebo-controlled trial on adults with non-alcoholic fatty liver disease, reductions in serum cortisol were identified after 8 weeks of curcumin supplementation [117].

Neuroprotection and Neuroplasticity

Blood–Brain Permeability

The blood–brain barrier (BBB) acts as a highly regulated interface that shields the brain from toxic substances in the blood, supplies brain tissues with nutrients, and filters harmful compounds from the brain back to the bloodstream [118]. Alterations in the BBB can lead to increased infiltration of peripheral material into the brain, culminating in neuroinflammation and oxidative stress. Perturbations in BBB regulation may contribute to the development of psychiatric disorders, including depression [119-121]. In vitro and animal studies have demonstrated that curcumin can protect the integrity of the BBB after ischemic stroke injury [122], cerebral ischemia-reperfusion injury [123], subarachnoid haemorrhage [124], and hypoxia [125].

Neurotrophins

Neurotrophins such as brain-derived neurotrophic factor (BDNF) and nerve growth factor are a family of proteins that support the survival, development and function of neurons [126]. The neurotrophic hypothesis of depression proposes that abnormalities in neurotrophin concentrations lead to neuronal atrophy and decreased neurogenesis, resulting in mood disorders. This theory is supported by findings of lowered concentrations of serum and plasma BDNF in patients with depression and the ability of many pharmaceutical antidepressants to increase BDNF concentrations [127, 128]. Results from animal stress models have confirmed curcumin can increase concentrations of BDNF [23, 29, 34, 129, 130]. Increases in peripheral BDNF have also been identified in several human trials. In a meta-analysis of four human randomised control trials comprising 139 participants, curcumin supplementation for 8–12 weeks significantly increased serum BDNF levels [131]. In a randomised, double-blind, placebo-controlled trial of adults with depression, the adjunct administration of curcumin with pharmaceutical antidepressants for 6 weeks was associated with greater increases in serum BDNF compared with placebo [60].

Neuroinflammation

Astrocytes are the most abundant glial cells in the central nervous system (CNS) and are responsible for a wide variety of complex and essential functions in a healthy CNS, including having roles in synaptic transmission, the preservation of brain homeostasis, trophic support, and the modulation of neuronal circuits [132]. Disturbances in astrocytic function are involved in the pathogenesis of neurodegenerative diseases and can contribute to an overactive inflammatory/immune response in the CNS. Evidence from post-mortem human brain tissues has demonstrated changes in glial cell morphology, density, and astrocyte-related biomarkers and genes in mood disorders [133]. It has also been observed that multiple brain regions in individuals with depression have reduced astrocyte densities [134]. An increasing number of studies have confirmed that curcumin is capable of directly inhibiting activated astrocyte activity, inflammation in astrocytes, and significantly increasing astrocyte survival after oxidative stress [135-138].

Microglia are another type of glial cell that make up the innate immune system of the CNS and are key cellular mediators of neuroinflammatory processes [139]. In addition to releasing inflammatory mediators, microglia can also secrete glutamate and metabolise kynurenine transported to the CNS into quinolinic acid, a neurotoxic compound [140]. Studies have revealed overactive microglia in patients with depression, with even greater activity in suicidal patients [141]. Studies have suggested that during stress and pathologies, microglia play a significant role in disrupting neuroplasticity and have detrimental effects on neuroprotection, causing neuroinflammation and an exacerbation of depression [139]. Curcumin can inhibit microglia transformation and associated inflammatory mediators such as IL-1β and TNFα, and mitigates neuroinflammation by modulating microglia polarisation [47, 100, 142, 143]. Curcumin administration also has protective effects against quinolinic acid-induced neurotoxicity [144, 145].

Mitochondrial Activity

Mitochondria are cellular organelles involved in energy production and several other biological processes, such as regulating oxidative stress and apoptosis. A relationship between mitochondrial dysfunction, characterised by impairments in energy production and increased oxidative stress and depression, has been reported in a wide range of studies on cell cultures, animal models, and clinical research [146-149]. Consequently, interest in treatments that target mitochondria dysfunction is on the rise. Findings from in vitro and in vivo studies have indicated curcumin can protect neuronal cells against mitochondrial pathology in a wide range of neurodegenerative-inducing stressors such as cerebral ischemia, and exposure to neurotoxic compounds such as methamphetamine, alcohol, rotenone, hydrogen peroxide, glutamate, interferon-γ and aluminium [150-155]. It has been reported that curcumin exerts its mitochondria protecting properties by retaining the activities of mitochondrial electron transport chain complexes and Bax/Bcl-2 ratio; enhancing mitochondrial fusion activity, mitochondrial biogenesis, and synaptic proteins; reducing fission machinery and mitochondrial swelling; reducing lipid peroxidation, protein carbonylation, and levels of oxidised lipids in the brain; reducing apoptosis, cytochrome c, caspase-3 and -9 activation, and mitochondrial depolarisation; reducing concentrations of TNFα, IL-1β and other inflammatory cytokines; modulating phosphoCREB-BDNF signalling and nuclear factor-erythroid factor 2-related factor 2; and restoring glutathione levels and superoxide dismutase activity [150, 156].

Intestinal Microbiota and Permeability

The gut–brain axis (GBA) refers to a bidirectional communication between the gastrointestinal tract and the CNS involving the neural, endocrine, and immune pathways. Disturbances in the GBA have been identified in depression, including changes in the composition of intestinal microbiota and increased intestinal hyperpermeability [157, 158]. Because processes within the GBA can influence HPA-axis activity, neurotransmitter production, BDNF production, and the immune response, it is increasingly recognised as a target of intervention for the treatment and prevention of depression [159, 160]. Despite curcumin having low oral bioavailability, therapeutic effects from curcumin have been observed in a wide array of conditions. It has been postulated that curcumin’s benefits may be derived via its effect on the gastrointestinal system; namely, its influence on intestinal microbiota, intestinal permeability, and gut inflammation and oxidative stress [161]. In a cell-culture model, tight junction redistribution and an increased inflammatory response was ameliorated by curcumin after exposure to Campylobacter jejuni (a common cause of foodborne gastroenteritis) [162]; and in mice exposed to a high-fat diet, curcumin upregulated the expression of intestinal tight junction proteins, occludin and zonula occluden-1 [163]. Moreover, in a human trial, 3 days of curcumin supplementation reduced gastrointestinal barrier damage during exertional heat stress in non-heat-acclimated adults [164]. There is also increasing research demonstrating curcumin can influence the composition of gut microbiota. In mice fed a high-fat diet, curcumin altered gut microbiota by increasing the relative abundance of the Lactococcus, Parasutterella, and Turicibacter genera [165]. In a rat uric acid nephropathy model, curcumin treatment protected against the overgrowth of opportunistic pathogens, including Escherichia-Shigella and Bacteroides, and increased the relative abundance of bacteria producing short-chain fatty acids, such as Lactobacillus and Ruminococcaceae [166]. Moreover, in asthma-induced mice, curcumin altered the composition of gut microbiota characterised by a significant decrease in the Firmicutes to Bacteroidetes ratio and reduction in the relative abundances of proinflammatory bacteria, such as Proteobacteria, Intestinimonas, unidentified Ruminococcaceae, and Lachnospiraceae [167]. In a human trial, the number of taxa detected increased by 69% in participants consuming curcumin for 8 weeks, compared with a 7% increase and 15% decrease in participants administered turmeric or a placebo. However, in an 8-week trial in adults with self-reported digestive complaints, curcumin administration did not significantly alter the composition of gut microbiota compared with placebo [77].

Other Biological Activities

Leptin

Differences in concentrations of leptin have been identified in depression, comprising findings of both increased and decreased concentrations [168-171]. In a meta-analysis based on four human trials, it was confirmed that curcumin lowers plasma leptin concentrations [172]. Understanding the role of leptin in depression requires further investigation; however, curcumin’s influence on leptin and possibly leptin receptor sensitivity and leptin resistance present as another potential mechanism of action.

Insulin and Blood Sugar Regulation

Disturbances in blood sugar regulation, insulin concentrations, and insulin resistance have been identified in depression [173, 174]. Although the administration of antihyperglycaemic agents, including metformin and peroxisome proliferator-activated receptor-γ (PPARγ) receptor agonists, have yielded inconsistent findings in depression studies, insulin signalling has been shown to influence serotonergic transmission [173, 174]. Based on a meta-analysis of four trials and 453 participants, it was concluded that curcumin supplementation may assist in improving insulin resistance and glycaemic control [175].

The Endocannabinoid System

The endocannabinoid system (ECS) is a neuromodulator system that has a significant influence on the CNS and the inflammatory reaction to endogenous and exogenous compounds. The ECS also influences anxiety, feeding behaviour, emotional responses, HPA-axis activity, and neurogenesis [176, 177]. Alterations in the ECS have been identified in depression and present as a therapeutic target of intervention [177, 178]. In animal trials, curcumin administration has influenced the ECS by increasing cannabinoid receptor type 1 (CB1)-mediated endocannabinoid signalling and increasing levels of CB1 mRNA [42, 179].

Sex Hormones

Even though findings are inconsistent, a relationship between sex hormones such as estrogen and testosterone and depression has been identified [180, 181]. Curcumin can influence multiple pathways associated with estrogen receptor expression and signalling [182, 183], and, in an animal study, ameliorated fluoxetine-induced reductions in testosterone [184] and influenced the activity of 17β-hydroxysteroid dehydrogenase, an enzyme involved in the biosynthesis of testosterone [185].

Docosahexaenoic Acid Synthesis in the Brain

There is an increasing body of evidence confirming a relationship between low omega-3 polyunsaturated fatty acids status and depression [186]. Docosahexaenoic acid (DHA) is the most prevalent omega-3 fatty acid in brain tissue and is critical for brain development and health [187]. In an animal study, compared with the administration of α-linolenic (ALA) alone (a precursor to DHA), its delivery in combination with curcumin enhanced the synthesis of DHA, elevated levels of enzymes involved in the synthesis of DHA such as fatty acid desaturase 2 and elongase 2, and increased DHA concentrations in both liver and brain tissue. Furthermore, treatment with curcumin and ALA reduced anxiety-like behaviour in rodents [188].

Clock Gene Expression

After alterations to light/dark cycles, stress and anxiety-like behaviour were significantly increased in mice. However, the concurrent administration of curcumin ameliorated these behavioural changes and modulated the expression of the Period Circadian Regulator 1 (PER1) gene [189]. In other animal studies, age-induced alterations in the daily rhythms of clock genes were restored by curcumin administration [190, 191]. The PER1 gene and other clock genes are involved in biological processes such as feeding behaviour, sleep deprivation and vulnerability to depression [192-195].

Safety and Tolerability of Curcumin

In human trials, curcumin has been well tolerated with the frequency of self-reported adverse effects often similar to placebo administration. The most common adverse effects include mild gastrointestinal discomfort such as nausea, mild abdominal pain and diarrhea [69, 70]. A summary of adverse effects reported in depression trials are detailed in Table 2. In a search conducted in January 2022 on the US FDA website, three curcumin extracts had received approval by the FDA as ‘generally recognised as safe’ [196]. Moreover, good tolerability and safety profiles have been shown in clinical trials, even at doses between 4000 and 8000 mg/day [197]. However, curcumin may increase the risk of bleeding in people taking warfarin and antiplatelet drugs, and can potentiate the effect of other medications such as antibiotics, anti-inflammatories, and chemotherapy agents, therefore some caution is warranted when used in combination with these medications [3, 198]. Human trials examining the chronic administration of curcumin are limited; however, in preclinical systematic safety studies commissioned by the National Cancer Institute, no toxic effects were identified at doses of 3.5 g/kg administered for 3 months to rats, dogs and monkeys [199].

Conclusions and Directions for Future Research

There is an increasing body of research supporting the efficacy of curcumin as a treatment for depression. These antidepressant effects have been demonstrated in both animal and human trials and have been confirmed by several meta-analyses [68, 69]. However, further research comprising larger sample sizes, depression subtypes and severities, and administered as a stand-alone or adjunct treatment is required. As summarised in Fig. 1, the antidepressant effects of curcumin may occur via several mechanisms; however, further investigations are needed to provide a more definitive understanding of the antidepressant processes associated with curcumin. Moreover, it will be important to understand if curcumin has greater mood-enhancing effects if administered to adults with depression presenting with biological disturbances that could be ameliorated by curcumin administration. For example, given curcumin’s anti-inflammatory effects, it will be important to determine if it will have greater efficacy in people with depression presenting with elevated markers of inflammation. In the study by Lopresti et al. [62], larger treatment effects were identified in people with atypical depression, which is often accompanied by higher peripheral inflammation.

Clinical trials to date have lasted 4–16 weeks, therefore the efficacy and safety of longer-term curcumin intake require further investigation. Treatment doses have also differed substantially, and optimal treatment doses have not yet been identified. Moreover, understanding the effects of curcumin administered before or during times of stress, or delivered as a treatment for the prevention of depression in people at high risk of depression, will be helpful. This will be a valuable area of investigation, as, in most animal trials, curcumin was delivered before exposure to a stressor, and in one trial had no antidepressant/anxiolytic effects when it was delivered after stress exposure [22]. Given curcumin’s anxiolytic effects in animal studies, and findings of anxiety reductions in clinical trials in depressed populations, an examination into its influence on anxiety symptoms in people presenting with anxiety disorders, experiencing high stress, and/or with comorbid depression and anxiety will be important. The anti-stress effects of curcumin in human experimental stress models such as the Maastricht Acute Stress Test or Trier Social Stress Test model may help to clarify some of the physiological mechanisms associated with curcumin [200, 201]. Finally, because of curcumin'’s poor oral bioavailability, various extracts have been formulated with greater bioavailability. However, despite confirmation of increased oral bioavailability, head-to-head comparisons of the antidepressant efficacy of these extracts have not been undertaken [1]. Such trials will be important to determine if different extracts impact safety, tolerability, and antidepressant outcomes. In conclusion, the results from studies to date confirm curcumin as a promising treatment for depression, but further research in this area is essential.

Evidence from animal and human trials confirms curcumin is a promising treatment for depression.

Curcumin has multiple biological actions that may account for its antidepressant effects.

More research is required to increase the understanding of the antidepressant effects of curcumin.