View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Crossref Journal of Cognitive Enhancement (2018) 2:106–113 https://doi.org/10.1007/s41465-017-0061-0 ORIGINAL ARTICLE A Combination of Nootropic Ingredients (CAF+) Is Not Better than Caffeine in Improving Cognitive Functions S. Caldenhove1 & A. Sambeth1 & S. Sharma1 & G. Woo1 & A. Blokland1 Received: 21 July 2017 /Accepted: 30 November 2017 /Published online: 18 December 2017 # The Author(s) 2017. This article is an open access publication Abstract Many nootropic compounds claim to have positive effects on cognitive performance. In this study, we tested the effects of the nootropic compound CAF+ on cognitive functioning. CAF+ contains a combination of ingredients that has separately shown to boost cognitive performance, including caffeine, l-theanine, vinpocetine, l-tyrosine, and vitamin B6/B12. We examined whether CAF+ would improve cognitive functions in healthy young participants, and whether it would be more effective than caffeine. We used a randomized double-blind placebo-controlled three-way cross-over design to examine the performance of 21 healthy young participants on a test battery aimed to measure memory performance, attention, and sensorimotor speed. Our main outcome measure was participant’s performance on the Verbal Learning Test (VLT). Subjective alertness, heart rate, and blood pressure were also monitored. Participants were tested at 30 and 90 min after treatment. We found that after 90 min, the delayed recall performance on the VLTafter caffeine was better than after CAF+ treatment. Further, caffeine, but not CAF+, improved the performance in a working memory task. In a complex choice reaction task caffeine improved the speed of responding. Subjective alertness was increased as a result of CAF+ at 30 min after administration. Only caffeine increased diastolic blood pressure. We conclude that in healthy young students, caffeine improves memory performance and sensorimotor speed, whereas CAF+ does not affect the cognitive performance at the dose tested. Keywords CAF+ . Caffeine . Cognition . Memory . VLT Introduction Nootropics, also known as smart drugs, are compounds that coffee and caffeine have been found to have beneficial effects enhance cognitive performance. There are two types of (Einöther and Giesbrecht 2013), there is still a further potential nootropics: synthetic or natural compounds. While both have to improve cognitive functions. been widely researched and can effectively increase functions Other natural ingredients have been suggested to have ben- such as memory and attention, natural nootropics are associ- eficial effects on cognitive functions. One example is ated with a safer side-effect profile and are even capable of vinpocetine (a semisynthetic derivative of the vinca alkaloid making the brain healthier (see Suliman et al. 2016). vincamine, extracted from the plant Vinca minor), which has There is quite some experimental evidence demonstrating been shown to improve memory functions in humans (Subhan that the natural ingredient caffeine has positive effects on cog- and Hindmarch 1985). Vitamins B6 and B12 have also been nitive functions in healthy volunteers. This has been shown in found to have positive effects on brain functions in healthy young (e.g., Hogervorst et al. 1999) as well as old subjects subjects (Bryan et al. 2002). Interestingly, the amino acid ty- (Lorist et al. 1995). Caffeine is considered to be safe, within a rosine, which is a precursor of dopamine, has been shown to certain dose range, and can easily be administered. Although exhibit both cognition-enhancing as well as stress-reducing effects (Banderet and Lieberman 1989; Brady et al. 1980; Deijen and Orlebeke 1994). A similar effect is suggested for * S. Caldenhove l-theanine (Nathan et al. 2006), although its combined effects [email protected] with caffeine are more extensively researched. L-theanine is well known for its synergistic effects with caffeine, leading to 1 Department of Neuropsychology and Psychopharmacology, larger improvements in cognition together than alone Maastricht University, Maastricht, the Netherlands (Camfield et al. 2014; Einother et al. 2010; Haskell et al. JCognEnhanc(2018)2:106–113 107 2008) and eliminates the vasoconstrictive effects of caffeine caffeine. This could have great potential for treating age- (Dodd et al. 2015). It should be noted that the study Dodd associated memory impairments such as dementia disorders. et al. does not show evidence of a synergistic effect of caffeine The primary objective of this experiment was to establish and l-theanine on cognition. However, relatively lower doses the effects of CAF+ on cognition, especially memory, in were used in their study compared to previous studies, which healthy adults. As our secondary objective, we have measured may suggest that the combined effects depend on the dose. performance on other cognitive tasks after CAF+: working It could be suggested that other combinations of natural memory performance using an n-back task, response inhibi- ingredients may also lead to synergistic effects, as with caf- tion and focused attention using the Stroop, complex scanning feine and l-theanine. This could be based on the assumption and visual tracking using the digit symbol substitution test that they work via unique molecular pathways which, when (DSST), and motor speed using a simple, choice, and incom- stimulated together, create an additive effect. For example, patible reaction time task. Another secondary objective was to caffeine is assumed to work via an adenosine mechanism establish that potential performance differences were concom- (Einöther and Giesbrecht 2013), whereas vinpocetine has itant with, but not primarily due to mood changes. The Bond been suggested to act via a phosphodiesterase type 1 mecha- and Lader evaluation form was used to measure the subjective nism (Filgueiras et al. 2010). Another possibility is that the state and perceived alertness (McNair et al. 1971). Finally, effects of certain nootropics may improve the efficacy of blood pressure and heart rate were measured to evaluate drug others. As mentioned, the anti-sympathetic properties of l- effects on these basic physiological parameters. theanine may allow caffeine’s arousal-inducing effects to be more potent (Dodd et al. 2015). This can be related to the well- known inverted U-shaped relation between stress/arousal and Methods cognitive performance (Baldi and Bucherelli 2005), in which case, it is possible that the effects of l-theanine place partici- Participants pants more optimally on this curve for the specific task at hand. As l-tyrosine may also exhibit stress-protective effects, All experimental procedures were approved by the Medical combining it with an arousal-inducing nootropic may also Ethics Committee of Maastricht University and performed in improve participant’s efficacy on a cognitive task. Finally, it accordance with the 1975 Declaration of Helsinki, as revised could be possible that a combination of different nootropics in 2008. Twenty-one healthy participants (10 male, 11 female; affects entirely different pathways than those that they affect mean = 21.7, SD = 3.1, range = 18–31) were included. The when administrated separately. participants were recruited from Maastricht University via ad- For these reasons, it would be interesting to combine a num- vertisements. They were screened with a medical question- ber of natural nootropics and investigate their effect on human naire and a urine hCG level test, to exclude pregnancy. cognition. Indeed, several natural nootropic blends exist and are Other criteria which excluded participation in this study were: available on the market. The main problem with these blends is having a (history of) cardiac, hepatic, renal, pulmonary, neu- that the ingredients are often separately known to have rological, gastrointestinal, hematological, or psychiatric ill- cognition-enhancing effects, but regarding their combined ef- ness. With regard to the psychiatric illness, those volunteers fects, the experimental evidence from randomized controlled who have suffered from depression, bipolar disorder, anxiety trials is lacking. With the current study, we tackle part of the disorder, panic disorder, psychosis, or attention deficit hyper- problem by investigating one of these nootropic blends. activity disorder were excluded from participation. Also, those We used a randomized, double-blind, placebo-controlled volunteers with a first-degree relative with a psychiatric dis- three-way cross-over design to examine the effects of the nat- order or a history with a psychiatric disorder were excluded. ural nootropic blend CAF+ on cognitive markers of memory Other exclusion criteria were excessive drinking (> 20 glasses and attention, and on mood and physiology. CAF+ contains of alcohol-containing beverages a week), lactation, use of 100 mg caffeine, 200 mg l-theanine, 40 mg vinpocetine, medication other than oral contraceptives, use of recreational 300mgl-tyrosine,1mgvitaminB12, and 20 mg vitamin B6. drugs from 2 weeks before until the end of the experiment, and These ingredients have different mechanisms of action and a any sensory or motor deficits which could reasonably be ex- possible additive effect on brain function. In order to evaluate pected to affect test performance. All participants had to sign the synergistic effects of this combination of different ingre- an informed consent form