We are not aware of any study to date which has directly compared the cognition enhancing effects of a nutraceuticals and a pharmaceutical in a head to head trial in healthy volunteers. The purpose of this review is to examine the literature describing clinical trials of the neurocognitive effects of modafinil, Panax ginseng and Bacopa monniera in order to compare their effect sizes across different cognitive domains.

As well as pharmaceutical approaches to cognitive enhancement, there is growing interest in the possibility that certain nutraceuticals may enhance cognitive performance. Herbal extracts may contain multiple active components which, in concert, may influence numerous neuronal, metabolic and hormonal systems involved in behavioural processes 4 . Additionally the interactions between these actives may be synergistic, resulting in complex dose and time dependent effects. These factors are challenging for psychopharmacology, making certain positive effects fragile even where there is strict batch to batch consistency across studies, and rendering negative findings sometimes difficult to interpret. Nevertheless there is growing evidence that certain standardized natural products have reproducible neurocognitive effects in humans, possibly because of their inherent polyphamacological properties. Examples of the most promising nutraceuticals in this context include species of Salvia (sage) 5 - 8 , Panax ginseng 9 - 12 and Bacopa monniera 13 - 17 . For the purposes of this short review we chose to concentrate on Ginseng and Bacopa. The former has been shown to enhance robustly cognitive performance after acute dosing 18 , whilst Bacopa has been shown to have nootropic effects with chronic dosing 16 .

Over recent years there has been increasing interest in the area of cognitive enhancement. This field has traditionally focused on the effects of so‐called nootropics in those with fragile cognition (e.g. those with age‐related cognitive decline, mild cognitive impairment or dementia). However in recent years the field of cognition enhancement has also embraced studies into cognition enhancement in young, cognitively intact individuals 1 . In the context of pharmaceutical cognition enhancers, methylphenidate and modafinil (Provigil) have taken centre stage 2 . Modafinil had been taken as a cognitive enhancer by around 10% of respondents to an online survey of the readership of the journal Nature 3 , though it is worth noting that this study may have a high response bias from individuals using cognitive enhancers.

Effect sizes were calculated on statistically significant data in order to assess the magnitude of effects. Effect sizes were calculated using Cohen's d 19 . The strength of clinical effects were defined as small: d = 0.2, medium: d = 0.5 and large: d = 0.8 effect sizes as defined by Cohen 19 . Chronic trials utilizing a repeated measures design were analyzed at endpoint and not mid‐points. Effect sizes are presented in Tables 1-3 . It should be noted that all treatment‐associated benefits (e.g. increased accuracy, shorter reaction times) are presented as positive effect sizes and impairments (e.g. more errors, slower reaction times) as negative effect sizes respectively.

The electronic databases SCOPUS, PubMed and PsychInfo were accessed in early 2012 (April). Key word searches were conducted by combining ‘Ginseng’, ‘Bacopa’ or ‘modafinil’ with ‘cognition’, ‘memory’, ‘neuropsychological’, ‘neurocognitive’ and ‘executive function’. Articles that did not relate to human cognitive trials were excluded as were articles that were not in English. Accepted articles were those that had completed double‐blind, randomized, placebo‐controlled empirical investigations on healthy human subjects using cognitive function as a primary outcome. Additionally studies were included only if they described an intervention with at least one arm assessing one of Ginseng, Bacopa or modafinil. In the case of Ginseng and Bacopa, only studies using ‘pure’ extracts were accepted, i.e. there were no other supplements present within the target nutraceutical arm. Furthermore, all extracts must have been used in isolation and not contaminated by co‐use of other supplements as adjunct interventions.

Chronic BM interventions generally produced the most consistent and largest effect sizes. These ranged from small to medium effect sizes for measures of attention and information processing tasks such as RVIP, Stroop and inspection time. Larger effect sizes were evident for auditory verbal learning tasks where the effect sizes ranged from d = 0.230 for delayed word pair memory to d = 0.950 for delayed word recall (AVLT 4 ) and d = 1.01 for protection from pro‐active interference during delayed memory (AVLT 3 ).

There was large variation in the effect sizes for Ginseng (Table 2 ). The largest effect size, d = 1.396, was for amelioration of self‐rated mental fatigue during heavily loaded cognitive processing. Regarding cognitive processing the largest effect size was for simple reaction time ( d = 0.860). Interestingly another measure, reaction time on the 3‐back working memory task, showed a large positive effect size ( d = 0.806) following acute Ginseng administration and also had the largest impairment d = −0.481 41 following dosing for 8 days. This raises the possibility of neuroadaptations to the neural substrates influenced by acute Ginseng administration with longer term dosing resulting in opposite effects to acute dosing.

With regards to modafinil, our analysis revealed small effect sizes on reaction time and small to large effect sizes on response accuracy during visual‐spatial working memory, as well as a dose‐dependent increase in effect size for stroop reaction times (Table 1 ). There appeared to be no cognitive costs (i.e. cognitive impairments in other domains) associated with these effects, with effect sizes ranging from d = 0.083 to d = 0.774 (for accuracy of visual spatial memory).

Human studies reveal consistent cognitive enhancement as a result of BM administration across young, old and impaired adult populations 48 . Unlike modafinil and Ginseng, Bacopa may not acutely improve cognitive functioning (although there are as yet unpublished reports of acute effects during more effortful cognitive processing). To date publications are restricted to effects which are evident only after chronic interventions (typically 12 weeks of a 300 mg daily dose), with no significant improvements occurring after a 5 week intervention 17 or acutely after 2 h 49 . The most robust effects of BM are on memory performance, including positive effects on learning and consolidation of target stimuli 17 , delayed recall 13 , total learning 14 , visual retention of information 15 and working memory 16 . There is also evidence that BM can improve speed of information processing in both the inspection time task and rapid visual information processing 16 , 17 . Using BM in an older population group (55 years and over) has shown improvements in executive functioning on the Stroop task and the mental control subtest of the Wechsler memory scale 13 , 14 . There are also tasks which appear to be unaffected by BM administration including working memory speed 17 , reaction time 13 , 16 , 17 and divided attention 13 . Effect sizes for significant findings restricted to those domains significantly affected by Bacopa are presented in Table 3 .

Bacopa monniera (BM), known as Bacopa or Brahmi, is a herb from the Scrophulariaceae family of plants which has been used for centuries in Ayurvedic medicine. BM has been shown to contain a complex mixture of constituents including alkaloids, saponins and flavonoids. The key constituents of Bacopa are thought to be the triterpenoid saponins, bacosides A and B 42 . These bacosides usually co‐occur, differing only their optical rotation, with the presence of bacoside B believed to be an artefact generated during the isolation of bacoside A 43 . Animal studies have shown BM to be an antioxidant 44 , memory enhancer 45 , antidepressant 46 and to reduce the concentrations of beta‐amyloid in a mouse model of Alzheimer's disease 47 .

Despite growing evidence supporting the efficacy of Panax ginseng (G115) in modulating cognitive processes following a single dose, only three empirical studies have directly investigated the cognitive and mood effects following more extended Ginseng ingestion periods (with only two of these studies using the standardized G115 extract). Two early studies revealed improved speed of performing a mental arithmetic task following 12 weeks administration of Panax ginseng (200 mg G115 day –1 ) in young volunteers 40 . The most recent, Reay et al . 38 , 41 found both positive and negative effects of 7 days dosing with G115. Whilst there were beneficial effects of the 400 mg dose on various measures of the 3‐back task there were also negative effects on reaction time limited to the 200 mg dose.

With regards to cognitive function, a number of controlled studies have identified both positive and negative behavioural effects. The most consistent finding, however, is one of improved secondary memory (i.e. declarative memory involving recollection) performance following extract G115 alone 10 , 36 , 37 and in combination with both Ginkgo biloba 37 and Paullinia cupana (guaraná) 36 . In addition, Panax ginseng (G115) has been shown to enhance aspects of working memory 38 , to improve mental arithmetic performance (in a task that loads heavily on working memory resources) 11 , 12 and to speed attentional processes 39 in healthy volunteers. These benefits to reaction time occurred without a concomitant cost to accuracy, precluding the possibility of a treatment related shift in the speed/accuracy trade‐off. One recent study has shown that acute administration of a standard extract of a different Ginseng species, Panax quinquefolius (American ginseng), which has a ginsenoside profile distinct from that of Panax ginseng , can also improve working memory performance 38 .

Over the last decade or so a number of studies have revealed that single doses of Panax ginseng (also known as Asian ginseng) can modulate aspects of cognitive function 9 such as brain activity as measured by electroencephalography 34 and peripheral blood glucose concentrations 11 , 35 , in healthy young volunteers. Most of these studies have used a standardized extract (G115) which contains an invariant 4% ginsenosides.

Ginseng refers to extracts from the Araliaceae family of plants. It is estimated that, in the US, Ginseng is the second most used psychoactive herbal product 31 . The active components are believed to be the ginsenosides, of which over 30 have been isolated, though many exist in trace amounts 32 . The chemical structure of these aglycone saponins can be used to classify the ginsenosides into three groups: the protopanaxadiol group (e.g. Rb1, Rb2, Rb3, Rc, Rd, Rg3, Rh2, Rs1), the protopanaxatriol group (e.g. Re, Rf, Rg1, Rg2, Rh1) and the oleanolic acid group (e.g. Ro) 33 .

In non‐sleep deprived adults, modafinil is associated with improvements in accuracy of pattern recognition and the stop signal task following 100 mg and 200 mg 23 , with several studies showing improvements in digit span with the 100 mg dose alone 23 , 24 . Furthermore, modafinil improved accuracy of an executive planning task (Stocking of Cambridge) 25 . Faster reaction times have also been shown across a range of tasks, notably the Stroop colour naming task of selective attention 23 , 24 , 26 , 27 . There are also numerous tasks that are unaffected by modafinil, regardless of dose, including trailmaking 28 , mathematical processing 26 , spatial working memory 24 , logical memory 27 , associative learning 29 and verbal fluency 30 .

As noted in a review by Repantis et al . 2 , as well as its use in the context of sleep disorders, there has been an increase in academics and office workers using modafinil as a cognitive enhancer. Research into the cognitive enhancing effects of modafinil generally falls into one of two types: studies in sleep deprived and non‐sleep deprived human subjects. These have typically compared doses of 100 mg and/or 200 mg doses against placebo. As modafinil is used as a treatment for excessive daytime sleepiness, there is a large body of research assessing cognitive effects in sleep‐deprived participant groups. However, the results from these studies are not comparable with the participant groups used to assess the cognitive effects of Bacopa or Ginseng so are not included here.

Modafinil (C 15 H 15 NO 2 S 20 ) is a pharmaceutical drug used as a licensed treatment for excessive daytime sleepiness associated with narcolepsy or shift‐work 2 . The mechanisms responsible for its effects remain largely unknown. It appears to exert a wide range of effects including via modulating catecholamine activity 21 . The human pharmacokinetic profile is known, with peak effects between 2–4 h after oral ingestion and a half‐life of 12–15 h 22 .

Conclusions

All three substances reviewed here exerted overwhelmingly positive effects on neurocognitive function across different cognitive domains. However, it must be made clear that this review has only looked at the statistically significant results and did not include the non‐significant results from studies into the neurocognitive effects of these substances. Modafinil had the strongest effects on speed of information processing and executive functioning. Ginseng exerts acute positive effects on secondary memory and more heavily cognitively loaded working memory tasks. Bacopa administration appears to predominantly enhance learning and memory, with effects restricted to chronic administration. The differential effects on cognitive domains presumably reflects different mechanisms of action of each substance. Modafinil has multiple effects on neurotransmitter systems including region specific increases in adrenergic, histaminergic and glutaminergic activity and decreased GABAergic activity 50. The mechanisms for BM are unknown, but there is evidence that it has pro‐cholinergic effects as suggested by the effects on inspection time and rapid visual information processing 17, 51 as well as anti‐oxidant and anti‐inflammatory properties. As might be expected from an extract with multiple components Ginseng has been reported to have multiple properties relevant to neurocognitive function. These include glucoregulation, modulation of cholinergic and dopaminergic activity as well as increasing nitric oxide synthesis 19. Whilst the purpose of this review was to compare nutraceuticals and pharmaceuticals, it is worth noting that the majority of the BM research presented here relates to chronic administration whilst the modafinil and Ginseng research is predominantly in the context of acute administration. However, the purpose of this review is to assess substances that enhance cognition.

With regards to modafinil, the results here show the cognitive enhancing effects of the substance on non‐sleep deprived subjects, rather than during the treatment of excessive tiredness in narcolepsy or after sleep deprivation. It is also worth noting that many research papers using non‐sleep deprived individuals have not adequately reported the cognitive results so we were unable to compute effect sizes for these studies (although this factor is by no means limited to modafinil research). Regarding the effects of Ginseng and Bacopa, research into herbal medicines brings its own difficulties. For example human studies into BM have used different products across trials. Whilst the manufacturers of all BM products included in our review claim standardization, compositions of individual treatments have not been compared. However, all extracts used in studies to date are reported to have standardized bacoside content to levels between 50–55%. All Ginseng studies included in Table 2 used the standardized extract G115.

This review is limited by the number of studies currently available. As the number of double‐blind, placebo‐controlled, randomized trials is rising, it is likely that future reviews will be able to compare particular groups of individuals such as those with specific cognitive dysfunction or particular age groups. At present, the number of available studies is too low to make such direct comparisons. Future research studies may wish to compare directly the differences of these substances in the same cohort. We are also aware that some of the research into nutraceuticals is not widely available through popular search engines such as those used for this review.

In conclusion the nutraceuticals Ginseng and Bacopa produced effect sizes for cognitive enhancement which were comparable with those seen for modafinil, albeit in different cognitive domains. Future studies should directly compare the cognitive effects of these agents in direct, head to head clinical trials. Furthermore, presentation and statistical analysis of results in certain research papers have made calculating effect sizes difficult in some instances. This is an issue that will need to be addressed in future studies into both pharmaceutical or nutraceutical research aiming to establish any cognitive enhancing effects of said interventions.