1. Introduction
There has been increasing interest in natural dietary supplements that may support healthy cognition. Among their many reported health benefits, preliminary evidence suggests that bioactive phytochemicals (e.g., polyphenols) may improve cognition, particularly in aging populations [
1,
2,
3]. However, few studies have assessed whether these outcomes generalize to real-world settings.
Whole coffee cherry extract (CCE) is a proprietary, safe, powdered extract of whole coffee cherries from
Coffea arabica with high levels of coffee polyphenols (for information on the quantification of polyphenols, please see [
4,
5,
6,
7]) and substantially low (<2%; <4 mg/dose) levels of caffeine. The high-polyphenol CCE material is produced by VDF FutureCeuticals, Inc. (Momence, IN, USA) (U.S. patent 7,815,959) using an ethanol/water food grade extraction protocol according to a proprietary process that assures adherence to carefully established specifications and standards. The CCE extract has been produced from several varieties of
Coffea arabica plants, with most recent sourcing from dedicated plantations in India. Decaffeination occurs as part of the production process for CCE. All batches of CCE are tested to ensure caffeine levels are negligible. CCE has been previously associated with increased serum concentrations of both circulating and exosomal brain-derived neurotrophic factor (BDNF), in addition to increased alertness and decreased fatigue [
8,
9] (please see U.S. patents 11,471,500 and 12,036,261). Mechanistically, BDNF represents one of several potential pathways through which CCE may support or even enhance brain health and/or function. Pre-clinical research has suggested that polyphenols, and coffee cherry products in particular, decrease inflammation through modulation of specific targets, and may also work through gut–brain-axis-dependent mechanisms [
10]. These mechanisms, along with evidence from other organ systems, provide plausibility that CCE could contribute to improvements in brain function.
Despite the mounting evidence, additional well-powered and well-designed studies are needed to more clearly understand the effects of CCE. Preliminary and pilot studies have demonstrated that CCE may improve several measures of cognition in older adults (i.e., 55–65 years of age) exhibiting mild cognitive decline, and that these improvements may be driven by distinct neurophysiological changes [
5,
11,
12]. For example, our lab found that a single acute 100 mg dose of CCE led to rapid changes in brain networks associated with working memory concomitant with improvements in performance on a common working memory task (
n-back) and a response inhibition task (Go/No-Go). Another, larger cohort study demonstrated longer-term effects at 100 mg and 200 mg total daily CCE dosages that emerged as soon as after 7 days and persisted over 28 days [
12].
Interestingly, all studies to date have been conducted in sterile, traditional laboratory environments, which by definition do not automatically lend themselves to real-world generalizability. Indeed, there has been recent discussion in the literature related to the deficiencies of traditional clinical models [
13,
14,
15]. Accordingly, we designed and conducted a first-of-its-kind remote clinical trial to assess both the acute and long-term effects of CCE. We leveraged a double-blind, randomized, placebo-controlled, two-arm design (i.e., placebo versus CCE). Participants were recruited from across the United States. Although the study was conducted for 28 days, of particular initial interest was whether or not the acute results from our previous study would replicate in a real-world environment. Consequently, at the beginning of the long-term study, we required the participants to perform a pre- (baseline) assessment and a single-dose, acute (one-hour post-administration) cognitive assessment. We hypothesized that the CCE group, after a single dosage of 200 mg, would show improved performance post-administration on both the working memory (i.e., that which lies between immediate recall and long-term memory and has as a primary feature the active use or processing of memory to reason, problem solve, and plan) and the inhibitory control tasks (i.e., one’s ability to refrain from responding to an automatic or prepotent stimulus), as reported in previous research studies. Furthermore, we hypothesized that the CCE group would show greater improvements over the course of the 28-day supplementation period. If true, the results would provide robust evidence for distinct cognitive improvements outside of a laboratory environment.
4. Discussion
Here, we present a novel remote clinical trial in which we demonstrate results that are concordant with previous, laboratory-based studies, while also extending the current literature. This clinical trial utilized a very diverse, generally healthy study population aged 40–65 years old that participated remotely and electronically from across the United States. As such, we expected more noise in the data, and considered whether we might observe smaller effect sizes compared to the similar studies previously conducted in a clinical setting due to the impacts of the ‘real-world’ testing environment that, by definition, would be less rigorously controlled and less consistent across subjects. As expected, the generated data was indeed somewhat noisier than what would be anticipated from a study conducted in a typical laboratory setting. In retrospect, and despite the larger N, taking all of the unexpected variables into consideration, this study demonstrated strong statistical trends that would likely have yielded even stronger results with additional participants. The outcomes nonetheless add significantly to the body of research related to the acute impacts of CCE.
Our current acute data support greater improvements in accuracy during the 1-back condition of the
n-back task. Also, we noted significant reductions in omissions when completing the acute 1-back task, which led to greater improvements in accuracy for the CCE group compared to the placebo group. This notable reduction in omissions may suggest the CCE participants avoided mentally “locking up” when faced with repeated, time-pressured response challenges. Furthermore, we demonstrated that whole coffee cherry extract showed greater reductions in omissions, and greater improvements in accuracy for the Go/No-Go task with regard to mean hit rate and a strong trend toward outperforming placebo in overall accuracy after a single-dose acute administration [
5]. These results are in alignment with our hypotheses that CCE would outperform placebo, in alignment with previous laboratory-based investigations.
We did note that the placebo group outperformed the CCE group acutely during the 0-back task. This may reflect psychological process differences, as the 0-back task is essentially a perceptual task focused on identifying a single item across a host of trials, and not a cognitive assessment. There was no difference in the longitudinal data. Comparatively, the 1- and 2-back conditions were true cognitive challenges, requiring participants to keep a running mental log (memory) of stimuli in order to perform the task correctly. Furthermore, the differences observed during the acute challenge 0-back condition are likely due to directional differences, and do not appear to reflect an effect of magnitude.
We did not find any significant interaction effects with regard to reaction time on any of the measures (i.e., in this case, both groups improved their reaction time), although, as reported earlier, we did observe reaction time improvements in the CCE group when compared to baseline. This is in contrast to statistically significant reaction time decreases that were reported in earlier non-acute studies longitudinally [
5,
12]. We are not entirely surprised by how the data presents here, given the different types of devices used to complete the task, coupled with the larger-than-average reaction time improvements observed in the placebo group compared to those observed in prior studies and, in particular, given the clear signal we saw acutely on improvements in accuracy for the CCE group. It is important to note that, unlike our generally healthy current study population, previous laboratory-based studies had older populations with reported cognitive decline. The current study extends the literature by using a younger population (ages 40–65) that was generally healthy without any cognitive impairments. Furthermore, the diversity of the current sample along with the design of the study is much more representative and inclusive than previous studies, increasing the generalizability of the results.
Our longitudinal results suggest that the CCE group decreased false alarms during the 1-back task, with significant differences emerging by Day 14. As mentioned, the acute 1-back proportion correct across all trials demonstrated a significant interaction, such that the CCE group outperformed placebo. Longitudinally, we saw a similar pattern that approached significance (
Figure 7). Together, this provides additional important evidence of CCE’s acute and longer-term efficacy related to cognition, especially given that this study was conducted outside of strict laboratory conditions that would be expected to potentially yield higher levels of effort, concentration, and focus that are not necessarily typical of the real world.
Despite the lack of interaction effects for the 2-back condition, both acutely and longitudinally, we did observe some notable main effects of treatment. Specifically, the 2-back proportion of correct non-target trials and the number of omissions demonstrated main effects of treatment. While follow-up univariate ANOVAs directed our attention toward baseline differences for both results, CCE had fewer longitudinal omissions at Day 21 and Day 28 compared to placebo. These results were similar to the main effects of treatment that were demonstrated for proportion of correct non-target trials across all conditions and also for the number of omissions across all conditions. However, in the case of omissions and proportion correct of non-target trials across all conditions, there were no baseline differences, suggesting that CCE had greater accuracy at Day 21 for both metrics, and additionally at Day 14 for omissions. Together, these data suggest that the CCE group had greater accuracy during the 2-back condition (and across all conditions) with regard to correct non-target trials as well as omissions.
These data provide replication and increase our understanding of the effects of CCE on working memory. It is important to emphasize that, other than the acute data gathered on Day 1 as reported earlier herein, the remainder of this study was focused upon measuring cumulative effects. This is why subjects were instructed to refrain from taking any study materials before engaging in their assessments throughout the balance of the study.
Several observations are worthy of note. First, we determined our estimated sample size a priori based on previous effect sizes that were determined in laboratory studies that were controlled very differently from the ‘real-world’ set-up we executed here. Based upon several of the observed strong longitudinal trends that approached significance (
Figure 8), a larger sample size might be necessary to detect the effect. We will take that into account when designing future protocols. Second, we may have underestimated the amount of “noise” we would encounter in the data. As partially anticipated, our remotely administered assessment data did have substantially more noise than earlier clinical settings due to numerous extraneous variables that are attendant to the “real world” and are absent in a laboratory clinical setting. In this study, subjects (a diverse group from across the United States) performed their assessments in their own homes, on their own equipment, and under different conditions. As such, future longer-term studies should consider these study protocol differences when pursuing a remote clinical trial. This complication was not as significant in the acute measures. However, the data became noisier over the 4-week longitudinal timeframe due, at least in part, to the many variables introduced by distanced, non-laboratory assessments, not to mention various technical challenges, web-enabled software glitches, and user errors. These challenges are inherent in a remote clinical trial (as they are inherent in real life), and do not necessarily represent weaknesses in the approach, but are, by their very nature, strengths that yield clinical data outcomes that are far more likely to align to a person’s real-life experience outside of the lab. The benefits (i.e., accessibility, increased generalizability, more diverse samples) are significant and should not be underestimated. Indeed, we perceive them as potentially necessary for the advancement of nutraceutical research.
Future investigation is needed to better understand the physiological mechanisms underlying the observed improvements in cognitive function. For example, studies have demonstrated the potential for coffee-cherry-derived products to alleviate brain inflammation in mice through inflammatory signaling pathways and the gut–brain axis [
10]. Other research has demonstrated neurophysiological changes through the use of neuroimaging [
5]. Still other research has suggested a role for brain-derived neurotrophic factor [
4,
34]. Comprehensive, multi-modal studies are necessary to better understand the neurophysiological mechanisms that may support improvements in brain function.
5. Conclusions
We believe that this current study is a contributory step towards transforming the clinical trial landscape, especially for brain health supplements. The world is full of supplements with positive outcomes in laboratory settings that do not fulfill their promises when taken in the messiness of real life. Future studies should expand on this line of inquiry by conducting adequately powered, accessible remote clinical trials that take into consideration, and recognize as beneficial, the difficulties and extraneous variables that are specific to conducting such trials that mirror much more closely real-life circumstances. Demonstrating real-world results that are consistent with, and expand, results obtained from previous laboratory-based studies provides more confidence that the effects of CCE on focus, attention, concentration, and accuracy are not merely a product of a sterile, artificial environment, but are in fact real effects that can be experienced at home.
Finally, we feel that these data serve to enrich the growing body of evidence that CCE may support and potentially enhance brain health and function in older adults. Given the burgeoning global interest in brain health supplementation, it is critical that more robust research efforts are devoted toward characterizing the nature and efficacy of these supplements. This is especially true given that many brain-health studies that have been conducted were observational, underpowered, and/or not generalizable because of the laboratory setting [
35]. A recent commentary has touched on the importance of conducting both rigorous laboratory studies as well as longer-term observational studies that increase generalizability and leverage tools that allow for improved assessment of study coherence [
35,
36,
37,
38]. Thus, our study provides an attempt to bridge this gap by using methodologies previously applied in controlled laboratory settings but now implemented in real-world situations to provide generalizable data.