Fermented Ginseng Improves the First-Night Effect in Humans

SLEEP STRUCTURE IS DISTURBED DURING SLEEP RECORDING IN A LABORATORY, PARTICULARLY ON THE FIRST NIGHT. IT IS PRIMARILY CHARACTERIZED BY shorter total sleep time (TST), reduced sleep efficiency, prolonged sleep latency, more awaking time after sleep onset, a larger percentage of stage 1 sleep, and a delay in the onset of the first period of REM sleep on the initial all-night polysomnography (PSG) recording when compared to recordings in subsequent nights. This phenomenon is known as the first-night effect (FNE).1,2 The FNE is induced by the stressful conditions of the sleep-recording environment, such as discomfort caused by the numerous electrodes, limitation of movement by gauges and cables, monitoring by experimenters, and the novelty of the recording laboratory.3 Many studies have reported that anxiety and stress disorders enhance FNE.4–6 Therefore, FNE can be considered to be general response induced by transient and/or chronic stress in humans. Ginseng (Panax ginseng, C. A. Meyer, Araliaceae) is one of the most popular herbs in oriental countries such as Korea, China, and Japan. The main ingredients of ginseng are ginsenosides, glycosides containing an aglycone (protopanaxadiol or protopanaxatriol) with a dammarane skeleton. Numerous researchers have contributed to the accumulation of evidence that ginsenosides are responsible for the pharmacological effects of ginseng including anti-stress or anxiolytic effects in animals7–10 and humans.11–13 Ginseng is orally ingested; therefore, its ingredients must meet gastric juices and digestive and bacterial enzymes in the intestines. Active ingredients thought to be involved in the sedative action of ginseng are protopanaxadiol-type ginsenosides like Rb1, Rb2, Rc and Rd.14 Orally ingested ginsenosides pass through the stomach and small intestine without decomposition by either gastric juices or liver enzymes into the large intestine, where ginsenoside is hydrolyzed by colonic bacteria followed by transit to the circulation: colonic bacteria cleave the oligosaccharide connected to the aglycone stepwise from the terminal sugar to generate the major metabolites, 20S-protopanaxadiol 20-O-beta-D-glucopyranoside (M1) and 20S-protopanaxatriol (M4).15,16 Accumulating evidence strongly suggests that the metabolites are the active molecules in the body.16 However, metabolite-producing potential of intestinal bacteria differ among individuals.17,18 During the course of screening bacteria for metabolite-producing potential, we discovered that Lactobacillus paracasei A22119 was successful in producing fermented ginseng (FG), including a rich source of M1. Thus, we hypothesized that FG may constitute a more efficient means of administration and may provide a more stable anxiolytic or anti-stress effect. The final goal of this study was to clarify whether FG administration can improve the FNE and therefore act as a useful functional herb. We performed chronic administration studies in both animal and human subjects because many human studies associated with anti-stress or anxiolytic effects of ginseng have been carried out chronically.11–13 Firstly, we confirmed whether FG has more of an anxiolytic effect than ginseng with behavioral testing in mice with chronic administration. To clarify the anxiolytic mechanism, we also quantified the mRNA expression related to GABAergic neurotransmission in the mouse brain. In human subjects, we then carried out 2 consecutive double-blind sleep recordings after one-week administration of FG or placebo. Before and after administration, subjects were completed psychological questionnaires, and samples were taken to analyze stress-sensitive markers.