This is first study to evaluate the acute mood and cognitive effects of P. quinquefolius (American ginseng) extract in humans. We found treatment-related improvements in cognitive performance and increased calmness in healthy young adults. Compared to a placebo, all doses of Cereboost™ were found to improve some aspect of cognition. The present study did not observe any effect of on blood glucose levels thereby ruling out any interpretation of the cognitive facilitation effects as being due to impact on glucose or insulin-mediated mechanisms.
All three active doses improved Corsi blocks performance compared with placebo at all post-dose time-points with the most beneficial effects being observed for the lower two doses. Other than this the most robust effects were observed for the 200 mg dose, (although all doses influenced cognition to some degree). Immediate Word Recall accuracy and numeric working memory speed were differentially improved by the 200 mg dose at all three post-dose time-points. Conversely alphabetic working memory speed was improved at all three time-points following the 100 and 400 mg doses. Choice Reaction Time accuracy was significantly improved following both 100 and 400 mg at 1 h post-administration. At 3 h post-administration 100 mg continued to improve performance, and at 6 h post-administration choice reaction time accuracy was significantly improved by all treatment doses compared with placebo. The differential dose- and time- effects may indicate differential sensitivity of biological systems to specific neural substrates affected by ginseng and its constituent ginsenosides.
Regarding mood effects, compared to placebo 100 mg Cereboost™ improved self-rated calmness at 3 h and 6 h following administration. As this is the first study to assess the effects of this extract on mood, few comparisons can be drawn with the existing research. However a number of studies have assessed the effect of P. ginseng
on mood using the same Bond Lader mood scale as the present study (Kennedy et al. 2001a
). Both 200 and 400 mg reduced alertness at 6 h (Kennedy et al. 2001a
) and calmness at 2.5 and 4 h (Reay et al. 2010
). Other studies have also reported reduced mental fatigue during sustained mental effort following P. ginseng
in healthy young individuals (Reay et al. 2005
). In the present study 100 mg Cereboost™ was associated with increased calmness ratings at later time-points. Previous research in rodents has shown that Ginseng saponins and Ginsenoside Rb1 inhibit the stress-induced increases in plasma corticosterone (Kim et al. 1998a
; Luo et al. 1993
) later found that this inhibitory action of Ginseng was blocked by a co-administered inhibitor of nitric oxide (NO) synthase, suggesting that ginsenosides may modulate the stress-induced hypothalamus–pituitary–adrenal response by inducing NO production in the brain. Clearly at present this interpretation is purely speculative (indeed we found no effect of ginseng on self-ratings of stress), but may merit further investigation.
The mechanism(s) by which extracts of Ginseng or individual components derived from Ginseng exert their effects on cognition are not known. A number of potentially complementary effects may be involved. For example neuroprotective effects of ginsenosides have been demonstrated in vitro (Rudakewich et al. 2001
) and in vivo. Such effects include protection of hippocampal CA1 neurons, reduction of infarct area (Zhang and Liu 1996
), reduced lipid peroxidation, scavenging of oxygen free radicals (Chen et al. 1987
) and preservation of local cerebral glucose utilisation (Choi et al. 1996
) following ischaemia in rodents. Increased NO synthesis has been proposed to underlie these neuroprotective effects. The enzyme NO synthase has been shown to be present throughout the brain with a particular prevalence in the cerebellum and is reported to be involved in hippocampal LTP (Salemme et al. 1996
) and general memory processes (Prast and Philippu 2001
). Kennedy and Scholey (2003
) note that it may be significant that following ginsenoside administration, the release of NO from endothelial cells has been shown to be specific to the Panaxatriol rather than the Panaxadiol ginsenosides (Kang et al. 1995
). Jin et al. (1999
) suggest that memory enhancing effects in rodents are restricted to extracts with a high ratio of Panaxatriol to Panaxadiol ginsenoside content. Indeed the present study has observed substantial memory enhancement using the extract Cereboost™, which has a high Panaxatriol to Panaxadiol ginsenoside content (see Fig. ).
While Ginseng and Ginseng saponins boast an array of neuroprotective effects it seems unlikely that these attributes would greatly benefit cognition acutely. It seems more likely that any neuroprotective effects might be more pronounced in chronic trauma and/or deficit populations. However the effects of Ginsengosides are not limited to neuroprotective effects. As well as increased NO-mediated blood flow (Kim et al. 1998b
), ginsenosides can increase choline uptake (Zhang et al. 1990
), acetylcholine release (Benishin et al. 1991
) and monoamine metabolism (Petkov 1990
) all of which may contribute to acute positive neurocognitive effects.
The data presented here demonstrate enhancement effects of P. quinquefolius
predominantly on working memory processes (Corsi blocks, and both numeric and alphabetic working memory). There is also some evidence of positive effects on short-term verbal declarative memory (immediate word recall) and attention (choice reaction time). Such findings tempt speculation about the neuroanatomical loci of these effects. As well as its well-documented role in long-term episodic memory (Eichenbaum and Cohen 2001
), there is increasing evidence that the hippocampus may be involved in working memory (Axmacher et al. 2009
) particularly, as in the tests used here, when multiple items are processed. However, if the effects here are largely driven by hippocampal activation we might expect a more pronounced effect on secondary memory above the enhancement of immediate word recall. Working and short-term memory systems are thought be localized to parietal, hippocampal and pre-frontal cerebral circuitry, with the pre-frontal cortex dealing with higher order working memory/executive functions including manipulating working memory (Gabrieli et al. 1998
; Goldman-Rakic et al. 1996
). Currently, there is a paucity of data regarding brain areas involved in the cognition-enhancing of effects of Ginseng, we hope that neuroimaging studies will soon reveal which areas are activated by Ginseng during cognitive processing.
It has been well documented that the cholinergic pathways projecting to the cerebral cortex and hippocampus play a key role in learning and memory. It has also been argued that the cholinergic system is a specific target for cognitively enhancing agents (Giovannini et al. 1995
). A number of studies have identified cholinergic properties associated with isolated ginsenosides. A direct interaction between Rg2 and nicotinic receptor subtypes has been observed (Sala et al. 2002
). Moreover Benshin (1992
) demonstrated modulation by Rb1 of acetylcholine release and reuptake, along with a number of choline uptake sites in the hippocampus, and to a lesser extent, the cortex. Both ginsenosides Rg1 (Zhang et al. 1990
) and Rb1 (Salim et al. 1997
; Zhang et al. 1990
) have also been shown to increase choline acetyltransferase levels in the rat brain. Scopolamine-induced deficits are attenuated by P. quinquefolius
in rodents (Sloley et al. 1999
). Protection against scopolamine-induced amnesia by P. quinquefolius
was most evident in trials where animals were required to remember the task learned the previous day. In the same study, it was observed that Ginseng increased choline uptake into synaptosomes prepared from rat brain. In the human brain crude extracts of P. ginseng
exhibited an affinity for both nicotinic and muscarinic receptors in cerebral cortex membrane (Lewis et al. 1999
). As discussed previously, the P. quinquefolius
extract profile has 2–3 times the ginsenoside content than the more commonly researched P. ginseng,
with the highest expression of Rb1 and Re. Thus the cholinergic system is one potential central mechanism of action on the enhancement of memory by Cereboost™. On the other hand, the RVIP task used here may been regarded as a prototypical cholinergic task, and we found no effect of the ginseng extract on this measure.
A second aim of the study was to assess the acute effects of P. quinquefolius
on glucoregulation on young healthy adults. The results of the present study show that, at least at the dosages used here American ginseng has no effect on blood glucose levels. Vuksan et al. (2000a
) previously observed that 300 mg P. quinquefolius
lowered blood glucose levels during a glucose challenge in both healthy and diabetic subjects. In that study, however, Ginseng administration lowered blood glucose levels only when taken 40 min prior to the glucose challenge in healthy individuals. Conversely, diabetic subjects experienced a fall in blood glucose either whether Ginseng was administered 40 min prior to, or concurrently with, the glucose challenge, suggesting that this effect is somewhat more robust in diabetic subjects (or at least that the temporal aspects are less important in that population). It is also noteworthy that in the Vuksan study there was a substantial age difference between the ‘healthy’ individuals (34
7 year) and the diabetic individuals (62
7 year) raising the possibility that the effect of P. quinquefolius
on blood glucoregulation is more robust in older individuals. In the present study the ‘healthy’ individuals were in their mid-20s, somewhat younger than those in the study by Vuksan's group. Additionally the largest body of research assessing the effects of Ginseng on peripheral circulating blood glucose in humans has tended to investigate chronic administration (Vuksan et al. 2008
; Vuksan et al. 2000b
). It would be of great interest to evaluate glucoregulatory properties would emerge with chronic dosing using cereboost™, and any relationship with neurocognitive effects of such a regimen.
It is worth noting that these findings should be treated with a degree of caution. Firstly, this is the first investigation into the neurocognitive effects of American ginseng. Clearly the study needs at least partial replication possibly with more focus on specific working memory processes. Secondly, given the exploratory nature of the study, no adjustment was made for multiple comparisons (although we did implement a number of safeguards against conflated Type 1 error). This follows the recommendations of Keppel (1991
) and is consistent with analyses utilised in a series of similar, acute dose-ranging studies (Haskell et al. 2007
; Kennedy et al. 2001a
; Kennedy et al. 2003
; Reay et al. 2005
; Scholey et al. 2008
; Tildesley et al. 2005
). We are aware that adjusting the alpha level to allow for multiple comparisons would have yielded fewer significant findings. On the other hand this should be balanced against the observation that for the majority of outcomes where there were significant differences, these were at all three time-points (and for Alphabetic Working Memory and Corsi blocks for two and three doses, respectively) suggesting that they are unlikely to have arisen from Type 1 errors.
Overall the findings of the present study were the first to demonstrate cognitive and mood enhancement following Cereboost™ administration. Furthermore cognition-enhancing effects of the extract were observed across a range of cognitive modalities at a range of dosages. The lack of glycaemic effects suggest that these effects can occur independently of changes in blood glucose, at least in healthy younger populations. Further research is required assessing the neurocognitive effects of P. quinquefolius in other populations (e.g. older individuals and those with cognitive problems) as well as evaluating the neurocognitive effects of chronic administration.