Systematic Review

1. 1 Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; [email protected]
2. 2 Congenital Heart Disease Study Group, Asian Society of Cardiovascular Imaging, Seoul 13572, Korea
3. 3 InnovaRad Inc., Taichung 407004, Taiwan
4. 4 Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; [email protected]
5. 5 Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 70101, Taiwan
6. 6 Institute of Clinical Medical Science, China Medical University, Taichung 404333, Taiwan; [email protected]
7. 7 Department of Psychiatry & Brain Disease Research Center, China Medical University Hospital, Taichung 404332, Taiwan
8. 8 An Nan Hospital, China Medical University, Tainan 709204, Taiwan
9. 9 Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung 811022, Taiwan; [email protected]
10. 10 Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804201, Taiwan
11. 11 Department of Psychology, College of Medical and Health Science, Asia University, Taichung 41354, Taiwan
12. 12 Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10048, Taiwan
13. 13 Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei-Hu Branch, Taipei 10845, Taiwan
14. 14 Center for Regional Anesthesia and Pain Medicine, Wang-Fang Hospital, Taipei Medical University, Taipei 11600, Taiwan

Citation: Tsai, I.-C.; Hsu, C.-W.; Chang, C.-H.; Tseng, P.-T.; Chang, K.-V. The Effect of Curcumin Differs on Individual Cognitive Domains across Different Patient Populations: A Systematic Review and MetaAnalysis. Pharmaceuticals 2021, 14,

* Correspondence: [email protected]; Tel.: +886-2-2312-3456

1235. https://doi.org/10.3390/ ph14121235

Abstract: Curcumin is a polyphenol with strong antioxidant and anti-inflammatory effects that has been shown to be effective in ameliorating cognitive decline in animal studies. However, its clinical effectiveness is inconclusive, and relevant gastrointestinal adverse events (AEs) have been reported. The aim of this meta-analysis was to summarize the existing evidence from randomized controlled trials (RCTs) of effects of curcumin on overall cognitive function, individual cognitive domains, and gastrointestinal AE. The study includes 8 RCTs and 389 participants. A random-effects model was used for the meta-analysis. Compared with the placebo group, the curcumin group was associated with an improvement in working memory (Hedges’ g = 0.396, 95% confidence interval (CI) = 0.078 to 0.714, p = 0.015) and a borderline benefit in processing speed (Hedges’ g = 0.303, 95% CI = 0.013 to 0.619, p = 0.06). In the domains of language, episodic memory/visual learning, verbal memory, cognitive flexibility/problem solving, and overall cognitive function, no significant difference existed for the comparison between the curcumin and placebo groups. The curcumin group had a significantly higher risk of gastrointestinal AEs than the placebo group (odds ratio = 3.019, 95% CI = 1.118 to 8.150, p = 0.029). In the future, the effects of curcumin on working memory, processing speed, and gastrointestinal AE should be further investigated.

Academic Editors: Víctor López and Filippo Maggi

Received: 8 November 2021 Accepted: 25 November 2021 Published: 28 November 2021

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Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Keywords: cognition; cognitive function; Curcuma longa; curcumin; turmeric

Pharmaceuticals 2021, 14, 1235. https://doi.org/10.3390/ph14121235 https://www.mdpi.com/journal/pharmaceuticals

1. Pharmaceuticals 2021, 14, 1235 2 of 18

1. 1.1. Curcumin in Cognitive Decline Animal Studies
2. 1.2. Curcumin in Cognitive Epidemiological Studies and Clinical Trials
3. 1.3. Individual Cognitive Domains and Gastrointestinal Adverse Events

The most important age-related changes occur in the domains of working memory, processing speed, and problem-solving (executive function) [18]. Alzheimer’s disease is characterized by a decline in working memory, episodic memory, and problem solving [19]. Schizophrenia is known for its multi-domain involvement, including working memory, verbal memory, attention, and executive function [20]. Since earlier human studies usually treat cognitive function as a whole [3,12], the effects of curcumin on different cognitive domains should also be further investigated.

Although curcumin is a safe natural compound that can be ingested up to 6 g/day for 4–7 weeks [21] without reported toxicity, side effects, such as gastrointestinal upset and diarrhea, have been observed [21–23]. The aim of this study was to review the available RCTs with their corresponding data in a trial registry to provide an updated meta-analysis on the effect of curcumin on overall cognitive function and individual cognitive domains. In this meta-analysis, we also analyzed the side effects and pertinent withdrawal rates of each included trial.

The PRISMA flow chart of the literature search process is presented in Figure 1. After removing the duplicated articles and excluding non-relevant articles by reading the titles and abstracts, we found 11 RCTs evaluating the effect of curcumin on cognitive function.

The PRISMA flow chart of the literature search process is presented in Figure 1. After removing the duplicated articles and excluding non-relevant articles by reading the titles

1. Pharmaceuticals 2021, 14, 1235 3 of 18

Two articles were excluded due to an intervention duration of less than 8 weeks [14,24]. One article was excluded because it was a review of an already-included RCT [25] (Table S3). Finally, eight articles were included [10,11,13,15,16,26–28]. The clinical trial registry data of these eight articles were also checked and analyzed for qualitative and quantitative analyses [29–35]. In this meta-analysis, all the data needed were successfully retrieved from published articles, accompanying Supplementary Materials, and clinical trial registries.

One article was excluded because it was a review of an already-included RCT [25] (Table S3). Finally, eight articles were included [10,11,13,15,16,26–28]. The clinical trial registry data of these eight articles were also checked and analyzed for qualitative and quantitative analyses [29–35]. In this meta-analysis, all the data needed were successfully retrieved from published articles, accompanying Supplementary Materials, and clinical trial registries.

Figure 1. PRISMA 2020 flowchart of current meta-analysis.

In these eight eligible RCTs, there were 389 participants with an age of 65.0 (mean) ± 10.2 (standard deviation) years and 44.7% (n = 174) males. All studies were double-blinded. The study duration ranged from 8 to 18 months. The enrolled subjects included older adults in four studies [11,15,27,28], patients with Alzheimer’s disease in two studies [10,13], and patients with schizophrenia in two studies [16,26]. The curcumin formulations were Theracumin® in three studies [15,16,26], Brain Active® in one study [28], Longvida® in one study [27], Biocurcumax® in one study [11], Curcumin C3 Complex® in one study [10], and powders of Kancor flavors or capsules of Arjuna Natural Extracts in one study [13]. The daily dose of curcumin ranged from 80 to 4000 mg.

In these eight eligible RCTs, there were 389 participants with an age of 65.0 (mean) ± 10.2 (standard deviation) years and 44.7% (n = 174) males. All studies were doubleblinded. The study duration ranged from 8 to 18 months. The enrolled subjects included older adults in four studies [11,15,27,28], patients with Alzheimer’s disease in two studies [10,13], and patients with schizophrenia in two studies [16,26]. The curcumin formulations were Theracumin® in three studies [15,16,26], Brain Active® in one study [28], Longvida® in one study [27], Biocurcumax® in one study [11], Curcumin C3 Complex® in one study [10], and powders of Kancor flavors or capsules of Arjuna Natural Extracts in one study [13]. The daily dose of curcumin ranged from 80 to 4000 mg.

The curcumin dosage, study arms, and cognitive function test results are summarized in Table 1. For studies with more than one test in a specific cognitive domain, the most representative test was selected by consensus and listed in the first line of the corresponding cells. For example, in Cox et al.’s study published in 2020 [27], there were serial seven subtraction, serial three subtraction, and virtual Morris water maze (vMWM) tests in the working memory domain. Serial seven was selected as the representative test because it had the best differentiating power [17,36]. In another example, in Ringman et al.’s study published in 2012 [10], ADAS-Cog and MMSE were used to assess overall cognitive function. We selected ADAS-Cog because it is more sensitive and detailed than the MMSE (Table 1) [37].

The curcumin dosage, study arms, and cognitive function test results are summarized in Table 1. For studies with more than one test in a specific cognitive domain, the most representative test was selected by consensus and listed in the first line of the corresponding cells. For example, in Cox et al.’s study published in 2020 [27], there were serial seven subtraction, serial three subtraction, and virtual Morris water maze (vMWM) tests in the working memory domain. Serial seven was selected as the representative test because it had the best differentiating power [17,36]. In another example, in Ringman et al.’s study published in 2012 [10], ADAS-Cog and MMSE were used to assess overall cognitive function. We selected ADAS-Cog because it is more sensitive and detailed than the MMSE (Table 1) [37].

Table 1. Summary of the retrieved trials investigating the effect of curcumin on cognitive functions.

Study Kuszewski et al. Cox et al. Kucukgoncu et al. Wynn et al. Small et al. Rainey-Smith et al. Ringman et al. Baum et al. Reference/ Registry (if available)

[35,38] [27,34] [26,33] [16,32] [15,31] [11,30] [10,29] [13] Year 2020 2020 2019 2018 2018 2016 2012 2008

Location Australia Australia United States United States United States Australia United States China

McCusker Alzheimer’s Research Foundation Hollywood Private Hospital Research Foundation

J. D. F. Alzheimer’s Disease Foundation Institute for the Study of Aging

NIH grants USDE contract Foundations Professorships

The State of Connecticut

CUHK Bupa Foundation

Blackmores Institute *

Not mentioned

Verdure Sciences *

Funding/grant

Design RCT, double-blind RCT, double-blind RCT, double-blind RCT, double-blind RCT, double-blind RCT, double-blind RCT, double-blind RCT, double-blind Allocation conceal

Research pharmacy

Independent investigator

Not mentioned

External staff Not mentioned Not mentioned Research pharmacy Not mentioned

Block randomization

Randomization table

Minimization method

Stratified Study duration 16 weeks 12 weeks 8 weeks 8 weeks 18 months 12 months 24 weeks 6 months

Not mentioned

Stratified Not mentioned Not mentioned

Randomization

Alzheimer’s disease Curcumin product

Overweight older adults

Non-demented older adults

Alzheimer’s disease

Healthy older adults Schizophrenia Schizophrenia

Subjects

Older adults

Brain Active® (Longvida®)

Powder or capsule Curcumin manufacturer

Curcumin C3 complex®

Longvida® Theracumin® Theracumin® Theracumin® Biocurcumax®

Kancor Flavors Arjuna Natural

Blackmores Verdure Sciences Theravalues Theravalues Theravalues Arjuna Natural Sabinsa

2 g/d curcuminoids (10) 4 g/d curcuminoids (9) Placebo (11)

1 g/d curcuminoids (8) 4 g/d curcuminoids (11) Placebo (8)

80 mg/d curcumin (42) Placebo (43) (12 weeks: 39/40)

180 mg/d curcumin (6) Placebo (6) (8 weeks: 5/5)

160 mg/d curcumin (31) Placebo (32)

360 mg/d curcumin (17) Placebo (19)

180 mg/d curcumin (21) Placebo (19)

1.32 g/d curcuminoids (39) Placebo (57)

Curcumin arms (N)

2 g/d: 76.7 ± 5.6 4 g/d: 75.3 ± 6.9 Placebo: 70.2 ± 12.4

1 g/d: 69.0 ± 10.9 4 g/d: 73.4 ± 6.6 Placebo: 77.8 ± 7.7

160 mg/d: 65.7 ± 1.4 Placebo: 65.8 ± 1.4

80 mg/d: 67.8 ± 6.0 Placebo: 68.4 ± 6.7

360 mg/d: 50.1 ± 9.6 Placebo: 50.9 ± 10.6

180 mg/d: 63.1 ± 8.4 Placebo: 62.9 ± 9.4

Age (years)

41.3 ± 12.7

66 ± 6.6

1 g/d: 12.5% 4 g/d: 27.3% Placebo: 37.5% Cognition domains NIH toolbox+ E-prime 2.0 MCCB MCCB Customized Customized ADAS-Cog & MMSE MMSE

2 g/d: 33% 4 g/d: 30% Placebo: 45%

160 mg/d: 48% Placebo: 44%

80 mg/d: 50% Placebo: 48.84%

360 mg/d: 64.7% Placebo: 100%

180 mg/d: 43% Placebo: 47%

1.32 g/d: 33.3% Placebo: 26.3%

Male %

Total: 75%

MoCA Non-computerized and Computerized composite scores

ADAS-Cog MMSE

MMSE

Overall Overall performance N/A Composite score MCCB T-score N/A

Serial 7 subtraction Serial 3 subtraction vMWM

Working memory Working memory

Working memory N/A N/A N/A N/A N/A

Trail making test part A

Wechsler digit symbol scale

N/A N/A Language Language N/A N/A N/A N/A COWAT N/A N/A

Processing speed Processing speed N/A Processing speed N/A

BVMT-R recall BVMT-R delay

Episodic memory /visual learning

N/A N/A N/A

Episodic memory N/A Visual learning N/A

RAVLT list A trial 1–5 total RAVLT short-term recall RAVLT delayed recall

BSRT CLTR BSRT total BSRT long-term storage

DATT recognition accuracy DATT response time

N/A N/A

Verbal memory Verbal memory

Verbal learning N/A

Cognitive flexibility/problem solving

Attention-vigilance Problem solving

Cognitive flexibility Arrow flankers test

N/A N/A N/A N/A N/A

Social cognition N/A N/A Social cognition N/A N/A N/A N/A N/A Fluid cognition Fluid cognition N/A N/A N/A N/A N/A N/A N/A

* Manufacturer of the tested curcumin product. ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive Subscale, BSRT: Buschke Selective Reminding Test, BVMT-R: Brief Visual Memory Test-Revised, CLTR: Consistent Long Term Recall, COWAT: Controlled Oral Word Association Task, CUHK: The Chinese University of Hong Kong, DATT: Divided Attention Tracking Task, J.D.F: John Douglas French, MATRICS: Measurement and Treatment Research to Improve Cognition in Schizophrenia; MCCB: MATRICS™ Consensus Cognitive Battery; MoCA: Montreal Cognitive Assessment, N/A: not available, NIH: National Institute of Health, RCT: Randomized Controlled Trial, USDE: United States Department of Energy, vMWM: Virtual Morris Water Maze.

2.2. Methodological Quality of Included Studies

Regarding the overall methodological quality of the studies included in the metaanalysis, 75% of the studies had low risk of bias, 12.5% had some risk of bias, and 12.5% had a high risk of bias (Figure 2). In a detailed assessment, one study was rated as “high” risk of bias in missing outcome data [11] and two studies were rated as “some” risk of bias in selective reporting [11,15]. Notably, we rated Wynn et al.’s study [16] as “low” risk of bias in all aspects, which was different from the assessment from Zhu et al.’s meta-analysis [39] in the domain of incomplete outcome data and selective reporting [12]. This was because Wynn et al. disclosed the full results on ClinicalTrials.gov after Zhu et al.’s article was published [32]. The reasons for rating “some” and “high” risk of bias are listed in Table 2.

Regarding the overall methodological quality of the studies included in the metaanalysis, 75% of the studies had low risk of bias, 12.5% had some risk of bias, and 12.5% had a high risk of bias (Figure 2). In a detailed assessment, one study was rated as “high” risk of bias in missing outcome data [11] and two studies were rated as “some” risk of bias in selective reporting [11,15]. Notably, we rated Wynn et al.’s study [16] as “low” risk of bias in all aspects, which was different from the assessment from Zhu et al.’s meta-analysis [39] in the domain of incomplete outcome data and selective reporting [12]. This was because Wynn et al. disclosed the full results on ClinicalTrials.gov after Zhu et al.’s article was published [32]. The reasons for rating “some” and “high” risk of bias are listed in Table 2.

0% 20% 40% 60% 80% 100%

Randomization process

Intervention adherence

Missing outcome data

Outcome measurement

Selective reporting

Overall risk of bias

Low risk of bias Some risk of bias High risk of bias

Figure 2. Summary of quality assessment of studies included in the meta-analysis using Cochrane risk of bias 2 tool.

Figure 2. Summary of quality assessment of studies included in the meta-analysis using Cochrane risk of bias 2 tool. Table 2. Detailed quality assessment of included studies using Cochrane risk of bias 2 tool. Kuszewski et al.

Baum et al. Reference/ Registry (if available)

Cox et al.

Kucukgoncu et al.

Wynn et al.

Small et al.

Rainey-Smith et al.

Ringman et al.

[35,38] [27,34] [26,33] [16,32] [15,31] [11,30] [10,29] [13]

Year 2020 2020 2019 2018 2018 2016 2012 2008 Randomization process

L L L L L L L L Intervention adherence

L L L L L L L L Missing outcome data

L L L L L H 3 L L Outcome measurement

L L L L L L L L

Selective reporting

L L L L 1 S 2 S 4 L L Overall RoB

L L L L 1 S H L L

H, high risk of bias; L, low risk of bias; RoB, risk of bias; S, risk of bias. 1 The assessment result is different from a previous meta-analysis

Overall

L L L L 1 S H L L

meta-analysis conducted by Zhu et al. [12], because the authors then published results on ClinicalTrials.gov (accessed on 13 August 2021) and provided full results online. 2 The outcome was assumed to be reported at baseline and at the 18month follow-up based on information from the trial registration website [31]. However, 6- and 12-month results were provided in the published article in addition to baseline and 18-month results [15]. Since we did not use the 6- and 12month data for meta-analysis, some risk of bias was considered. 3 This study was determined to have a high risk of bias in missing outcomes because many adverse event-related withdrawals were noted, especially in the curcumin group (21/80) compared with the placebo group (2/80). 4 The trial was registered for baseline and 12-month evaluations [30]. However, 6-month results were provided in the published article in addition to the baseline and 12-month results [11]. Since we did not use the 6-month data for meta-analysis, some risk of bias was considered.

conducted by Zhu et al. [12], because the authors then published results on ClinicalTrials.gov (accessed on 13 August 2021) and provided full results online. 2 The outcome was assumed to be reported at baseline and at the 18-month follow-up based on information from the trial registration website [31]. However, 6- and 12-month results were provided in the published article in addition to baseline and 18-month results [15]. Since we did not use the 6- and 12-month data for meta-analysis, some risk of bias was considered. 3 This study was determined to have a high risk of bias in missing outcomes because many adverse event-related withdrawals were noted, especially in the curcumin group (21/80) compared with the placebo group (2/80). 4 The trial was registered for baseline and 12-month evaluations [30]. However, 6-month results were provided in the published article in addition to the baseline and 12-month results [11]. Since we did not use the 6-month data for meta-analysis, some risk of bias was considered.

2.3. Primary Outcome 2.3.1. Overall Cognitive Function

2.3. Primary Outcome 2.3.1. Overall Cognitive Function

Six out of the eight enrolled studies had data on overall cognitive assessment. No statistical difference (Hedges’ g = 0.340, 95% CI = −0.353 to 1.033, p = 0.337, I2 = 0.0%) was observed between the curcumin and placebo groups (Figure 3).

Six out of the eight enrolled studies had data on overall cognitive assessment. No statistical difference (Hedges’ g = 0.340, 95% CI = −0.353 to 1.033, p = 0.337, I2 = 0.0%) was observed between the curcumin and placebo groups (Figure 3).

Figure 3. Forest plot of the effect of curcumin on the overall cognitive function.

The participants were further grouped into older adults, patients with Alzheimer’s disease, and patients with schizophrenia for subgroup analysis. However, regardless of the group, curcumin was no more effective than placebo in overall cognitive function (older adults: Hedges’ g = 0.740, 95% CI = −0.731 to 2.211, p = 0.324, I2 = 94.9%; Alzheimer’s disease: Hedges’ g = −0.326, 95% CI = −0.866 to 0.214, p = 0.237, I2 = 0.0%; schizophrenia: Hedges’ g = 0.511, 95% CI = −0.431 to 1.452, p = 0.288, I2 = 50.2%) (Figure S1).

The participants were further grouped into older adults, patients with Alzheimer’s disease, and patients with schizophrenia for subgroup analysis. However, regardless of the group, curcumin was no more effective than placebo in overall cognitive function

In the six studies analyzed, Rainey-Smith et al.’s [11] and Kucukgoncu’s [26] studies were the only two with ES more than 1.0, and were considered to be the source of heterogeneity.

2.3.2. Individual Cognitive Domains

With regards to the individual domains, working memory was the only domain with significant between-group differences. From the data of the three enrolled studies [26–28], the curcumin group significantly improved working memory compared with the placebo group (Hedges’ g = 0.396, 95% CI = 0.078 to 0.714, p = 0.015) without significant heterogeneity (I2 = 0.0%) (Figure 4).

the curcumin group significantly improved working memory compared with the placebo group (Hedges’ g = 0.396, 95% CI = 0.078 to 0.714, p = 0.015) without significant heteroge-

Pharmaceuticals 2021, 14, 1235 8 of 18

g p

Figure 4. Forest plot of the effect of curcumin on working memory.

Figure 4. Forest plot of the effect of curcumin on working memory.

Sensitivity analysis was also performed. In working memory, we selected a serial seven subtraction test to represent Cox et al.’s study [27], rather than serial three subtraction or vMWM tests. To confirm that the result was not affected by the decision, we used serial three subtraction and vMWM tests instead. The substitutions did not alter the statistical significance (serial three subtraction: Hedges’ g = 0.333, 95% CI = 0.016 to 0.650, p = 0.039, I2 = 0.0%; vMWM: Hedges’ g = 0.454, 95% CI = 0.135 to 0.773, p = 0.005, I2 = 0.0%) (Figures S2 and S3).

Sensitivity analysis was also performed. In working memory, we selected a serial seven subtraction test to represent Cox et al.’s study [27], rather than serial three subtraction or vMWM tests. To confirm that the result was not affected by the decision, we used serial three subtraction and vMWM tests instead. The substitutions did not alter the statistical significance (serial three subtraction: Hedges’ g = 0.333, 95% CI = 0.016 to 0.650, p = 0.039, I2 = 0.0%; vMWM: Hedges’ g = 0.454, 95% CI = 0.135 to 0.773, p = 0.005, I = 0.0%) (Figures S2 and S3).

g p = I2 g p I2

The processing speed in the curcumin group was also likely to be better than that in the placebo group with a borderline p value (Hedges’ g = 0.303, 95% CI = −0.013 to 0.619, p = 0.060, I2 = 19.5%) (Figure 5).

The processing speed in the curcumin group was also likely to be better than that in the placebo group with a borderline p value (Hedges’ g = 0.303, 95% CI = −0.013 to 0.619, p = 0.060, I2 = 19.5%) (Figure 5).

p g − p 2

Figure 5.Figure 5. Forest plot of effect of curcumin on processing speed.Forest plot of effect of curcumin on processing speed.

There was no statistical difference between the curcumin and placebo groups in the domains of language (Hedges’ g = −0.633, 95% CI = −1.878 to 0.612, p = 0.319, I2 = 93.0%; Figure S4), episodic memory/visual learning (Hedges’ g = −0.075, 95% CI = −0.438 to 0.287, p = 0.683, I2 = 0.0%; Figure S5), verbal memory (Hedges’ g = 0.273, 95% CI = −0.190 to 0.739, p = 0.248, I2 = 22.3%; Figure S6), and cognitive flexibility/problem solving (Hedges’ g = 0.050, 95% CI = −0.482 to 0.583, p = 0.853, I2 = 44.4%; Figure S7).

2.4. Secondary Outcomes

The curcumin group was likely to have a higher overall withdrawal rate than the placebo group, with a borderline p-value (OR = 1.643, 95% CI = 0.980–2.753, p = 0.059, I2 = 5.5%; Figure S8). The adverse event-related withdrawal rate and adverse event rates

were not significantly higher in the curcumin group, with an OR of 2.44 (95% CI = 0.791–6.361, p = 0.128, I2 = 45.1%) and 2.245 (95% CI = 0.803 to 6.276, p = 0.123, I2 = 46.5%), respectively (Figures S9 and S10). However, curcumin was associated with significantly more

5.5%; Figure S8). The adverse event-related withdrawal rate and adverse event rates were not significantly higher in the curcumin group, with an OR of 2.44 (95% CI = 0.791–6.361,

Pharmaceuticals 2021, 14, 1235 9 of 18

gastrointestinal adverse events than the placebo (OR = 3.019, 95% CI, 1.118–8.150, p = 0.029; I2 = 13.3%; Figure 6).

intestinal adverse events than the placebo (OR = 3.019, 95% CI, 1.118–8.150, p = 0.029; I2 = 13.3%; Figure 6).

Figure 6. Forest plot of the gastrointestinal adverse event rate of curcumin compared with the placebo group.

1. 2.5. Publication Bias Nopublicationbiaswasdetectedinanyfunnelplotundervisualinspection(Figures S11–S20).
2. 3. Discussion

1. 2.5. Publication Bias No publication bias was detected in any funnel plot under visual inspection (Figures
2. 3. Discussion

1. 3.1. Main Results
2. 3.2. Possible Mechanisms of the Improved Cognitive Function by Curcumin
3. 3.3. Evidence Summary of Multisystem Health Benefits of Curcumin

1. 3.1. Main Results
2. 3.2. Possible Mechanisms of the Improved Cognitive Function by Curcumin

There are multiple pathways related to the cognitive function improvement after the use of curcumin. Anti-inflammation is one of them, since there were studies showing that cognitive declines in schizophrenia and mood disorders were associated with inflamma-

Regarding the cardiovascular system, Ashtary-Larky et al. summarized nine RCTs and concluded that curcumin may reduce cardiovascular disease risk by improving glycemic and lipid profiles, scaling down inflammation, and reducing systolic blood pressure [44]. With reference to inflammatory diseases, such as ulcerative colitis, a metaanalysis of seven RCTs by Chandan et al. found that curcumin combined with mesalamine was associated with threefold better odds of a clinical response than mesalamine with placebo [45]. For physically active people and athletes, curcumin improved performance by reducing exercise-induced muscle damage and modulating the inflammation caused by physical activity, according to the systematic reviews of Suhett et al.’s and Fernández-

Lázaro et al. [46,47]. To enhance the effects of cancer therapy, Mansouri et al. systematically reviewed 22 studies, concluding that curcumin could reduce the side effects of chemotherapy or radiotherapy and improve patients’ quality of life [48].

Zhu et al. synthesized six RCTs and found that curcumin and placebo did not differ with respect to overall cognitive function. However, Zhu et al. did not investigate the effects of curcumin on different cognitive domains due to the limited number of available studies at that time. Our meta-analysis further divided the cognitive tests into different domains and found that curcumin could improve working memory and possibly processing speed.

These multi-system health benefits are related to antioxidant and anti-inflammatory activities and may also be synergistic [49]. For example, the positive cognitive effects might be related not only to the direct effects of curcumin on neural cells [50], but also to its action on the cardiovascular system, such as protecting the endothelium, maintaining microvascular function, stabilizing cerebrovascular perfusion, and keeping the brain–blood barrier intact [51,52], which can also ameliorate neurodegenerative changes [53].

1. 3.4. Effects of Curcumin on Different Cognitive Domains

The reason why working memory and processing speed improved more than other domains after the administration of the curcumin supplement may be related to its selective effect on different regions and cells.

Working memory is a unique, short-term active storage mechanism used to accomplish various cognitive activities [17]. Delayed-response tasks are usually used in animal studies to explore the relationship between working memory function and the underlying neural mechanism [17]. The studies of Watanabe et al. for monkey’s neural activity found that different working memory tasks activated overlapping prefrontal neural populations, and the magnitude of activity was related to the difficulty of the task [54,55]. The aforementioned findings indicate that working memory is mostly processed in the prefrontal cortex.

The protective effect of curcumin in the prefrontal cortex has also been demonstrated in animal models. Noorafshan et al. used three different neural damage rat models, including stress-induced, sulfite-induced, and sleep deprivation, and found that curcumin could prevent structural deterioration in neurons and glial cells, and could also counteract behavioral changes [8,56,57]. This showed that curcumin had a direct protective effect on the prefrontal cortex and may explain why curcumin was able to effectively improve working memory, as observed in our meta-analysis.

With regards to processing speed, the quantitative neuroimaging study of Magistro et al. on healthy young people found that the speed of processing was correlated with the volume of the white matter in the whole brain [58]. During the process of aging, a decreased overall processing speed and an increased variability of intra-individual processing speed has been observed in the elderly [59]. This decline in processing speed has been found to be accompanied by white matter changes on histopathology and neuroimaging [60,61]. The current cortical disconnection theory hypothesizes that a decline in white matter integrity disrupts the information flow within neural networks, which may be the cause of the reduction in processing speed [62,63].

Daverey et al. found that curcumin can inhibit hypoxia, inflammation, and apoptosis associated with white matter injury in rat cells [64]. Naeimi et al. used a rat model of demyelination and found that curcumin could significantly improve myelin repair and maintain white matter integrity [50]. These mechanisms may explain the beneficial effects of curcumin on the processing speed.

In contrast, using a literature search from the electronic database, we did not identify any animal or human studies demonstrating that curcumin could act on Broca’s area for language, occipital lobe for visual learning, fronto-temporo-parietal region for verbal memory, and the interaction between the thalamus and prefrontal cortex for cognitive flexibility. This may explain the non-significant results of curcumin for these cognitive domains.

1. 3.5. Adverse Gastrointestinal Effects of Curcumin
2. 3.6. Different Formulations and Ingredients
3. 3.7. Limitations

There are several limitations in our study. First, this meta-analysis synthesized different populations of participants, including older adults, and Alzheimer’s disease and schizophrenia patients. The differences in the underlying conditions might be associated with different cognitive changes under curcumin intervention. We performed a subgroup analysis to specifically address this issue, and found no significant difference among the three participant groups (Figure S1). Since the inflammation plays an important role in normal aging brain [80], Alzheimer’s disease [81], and schizophrenia [41], the antiinflammatory effects of curcumin seemed similar in the three aforementioned groups. Furthermore, a transdiagnostic meta-analysis is a common and acceptable practice if the potential heterogeneity is well-examined. For example, Zhu et al. included older adults, Alzheimer’s disease and schizophrenia patients to evaluate the effect of curcumin in cogni-

tive function [12], and Dauwan et al. included six different brain disorders to examine the effects of physical exercise on quality of life, depressive symptoms, and cognition [82].

Second, the number of eligible RCTs was small, resulting in only two to six datasets being extracted in each cognitive domain. Nevertheless, the significant benefit of curcumin in the working memory domain remained following the sensitivity analysis, indicating that the result was robust and not likely to be caused by the subjective decision of the index test.

Lastly, the RCTs in this field mostly employed the per-protocol design, which may inherently overestimate the treatment effect and underestimate the adverse-event-related dropout [83]. In this meta-analysis, we also used a per-protocol analysis to prevent distortion of the extracted data. In the future, for those who are designing a new RCT in this field, an intention-to-treat design is suggested to truly reflect the clinical effectiveness of curcumin.

1. 4.1. General Guidelines
2. 4.2. Database Searches and Identification of Eligible Papers
3. 4.3. Inclusion and Exclusion Criteria

The PICO (population, intervention, comparison, and outcome) setting of the current meta-analysis included: (1) P: human adult participants (≥20 years old); (2) I: curcumin oral supplement; (3) C: placebo; and (4) O: changes in the scores of the selected cognitive function tests.

To generate a recruited study list, the following inclusion criteria were used: (1) RCTs with adult human participants (≥20 years old), (2) RCTs investigating the difference in results of cognitive function tests after curcumin supplementation or placebo regimens, (3) RCTs with an intervention duration greater than or equal to 8 weeks, and (4) placebocontrolled trials. To be specific, we chose the least treatment duration of 8 weeks, which is the recommended length of curcumin supplement to take effect [88,89].

The exclusion criteria were as follows: (1) studies that were not RCTs; (2) studies that included participants <20 years old; (3) studies that did not investigate the influence of curcumin supplement and placebo regimens on cognition; (4) an introductory research review that simply reports previous studies; (5) studies with an intervention duration of less than 8 weeks; (6) studies that lacked placebo or controlled arms.

1. 4.4. Methodological Quality Appraisal
2. 4.5. Primary Outcomes (Changes in Cognitive Function)
3. 4.6. Secondary Outcomes (Withdrawal Rates and Adverse Event Rates)
4. 4.7. Data Extraction and Management
5. 4.8. Statistical Analysis

Based on the heterogeneous target populations in the recruited studies, the metaanalysis was conducted using a random-effects model [94]. The meta-analysis was performed using the Comprehensive Meta-Analysis software, version 3 (Biostat, Englewood, NJ, USA). We chose Hedges’ g and 95% confidence intervals (95% CI) as the main effect size (ES) of the primary outcomes (cognitive function changes in different domains). A Hedges’ g of 0.2, 0.5, and 0.8, was considered a small, moderate, and large ES, respectively [95]. We chose ORs and their 95% CIs to investigate secondary outcomes (rates of withdrawal and adverse events). Subgroup analysis was performed based on the differences in the target populations, such as older adults, Alzheimer’s disease, and schizophrenia. I2 and Cochran’s Q statistics were used to evaluate the degree of heterogeneity among the studies. I2 values of 25%, 50%, and 75% were considered low, moderate, and high heterogeneity, respectively [96].

If there was more than one test in a specific domain, the test that best discriminated the outcome change was selected for meta-analysis inclusion by consensus of two authors (I.-C.T. and K.-V.C.). For example, serial 7 and serial 3 subtraction tests were used for the evaluation of working memory [36]. Sensitivity analysis was also performed by substituting the representative test with other similar assessments and re-analyzed to check whether

the association between the intervention and outcomes changed significantly [91]. Potential publication bias was evaluated according to the Cochrane Handbook for Systematic Reviews of Interventions [97]. We visually inspected funnel plots when there were fewer than 10 datasets. Egger’s regression tests were performed when there were 10 or more datasets. A two-tailed p-value less than 0.05 was considered statistically significant.

Following at least 8 weeks of nutritional supplementation, curcumin was found to improve working memory more than a placebo regimen. The results in the cognitive domain of processing speed were notable, with a borderline p-value, which may be significant if further trials are included. Moreover, curcumin was associated with higher odds of gastrointestinal AEs than the placebo regimen. Future RCTs should be designed and reported under the intention-to-treat principle to better reflect the true effectiveness of curcumin in the real world.

Supplementary Materials: The following are available online at https://www.mdpi.com/article/ 10.3390/ph14121235/s1, Figure S1: Subgroup analysis forest plot of the effect of curcumin on overall cognitive performance grouped by the participants’ characteristics, Figure S2: Forest plot of the effect of curcumin on working memory using serial 3 as the index test in Cox et al.’s study, Figure S3: Forest plot of the effect of curcumin on working memory using virtual Morris water maze (vMWM) task as the index text in Cox et al.’s study, Figure S4: Forest plot of the effect of curcumin on language, Figure S5: Forest plot of the effect of curcumin on episodic memory/visual learning, Figure S6: Forest plot of the effect of curcumin on verbal memory, Figure S7: Forest plot of the effect of curcumin on cognitive flexibility/problem solving, Figure S8: Forest plot of the effect of curcumin on withdrawal rate compared with the placebo, Figure S9: Forest plot of the effect of curcumin on adverse event-related withdrawal rate compared with the placebo, Figure S10: Forest plot of the effect of curcumin on adverse event rate compared with the placebo, Figure S11: Funnel plot of the studies evaluating overall cognitive performance, Figure S12: Funnel plot of the studies evaluating working memory, Figure S13: Funnel plot of the studies evaluating processing speed, Figure S14: Funnel plot of the studies evaluating episodic memory/visual learning, Figure S15: Funnel plot of the studies evaluating verbal memory, Figure S16: Funnel plot of the studies evaluating cognitive flexibility/problem solving, Figure S17: Funnel plot of the studies evaluating withdrawal rate, Figure S18: Funnel plot of the studies evaluating the adverse event-related withdrawal rate, Figure S19: Funnel plot of studies the evaluating the adverse event rate, Figure S20: Funnel plot of the studies evaluating the gastrointestinal adverse event rate, Table S1: Excluded studies and reasons, Table S2: PRISMA Checklist, Table S3: Keywords and search results in different databases.

Author Contributions: Data curation, I.-C.T., P.-T.T. and K.-V.C.; formal analysis, I.-C.T. and K.-V.C.; investigation, C.-W.H., C.-H.C., P.-T.T. and K.-V.C.; methodology, C.-W.H., P.-T.T. and K.-V.C.; software, I.-C.T. and P.-T.T.; supervision, P.-T.T. and K.-V.C.; validation, C.-W.H., P.-T.T. and K.-V.C.; writing—original draft, I.-C.T.; writing—review and editing, C.-W.H., C.-H.C., P.-T.T. and K.-V.C. All authors have read and agreed to the published version of the manuscript.

Funding: This work was funded by National Taiwan University Hospital, Bei-Hu Branch; Ministry of Science and Technology (MOST 106-2314-B-002-180-MY3 and 109-2314-B-002-114-MY3); and the Taiwan Society of Ultrasound in Medicine. APC was funded by Ministry of Science and Technology and Taiwan Society of Ultrasound in Medicine.

Institutional Review Board Statement: This meta-analysis did not intervene or interact with humans nor collect identifiable private information, and thus does not require institutional review board approval.

Informed Consent Statement: Not applicable. Data Availability Statement: Data is contained within the article and Supplementary Files. Conflicts of Interest: The authors declare no conflict of interest.