The main active substance regarding the adaptogenic effects of R. rosea has been identified as salidroside, a phenylpropanoide derived from phenylethane [5, 30]. However, other compounds are also considered to be active adaptogenic constituents, including the phenylpropane rosavins [29, 31]. The stimulant and anti-stress actions of R. rosea and the glycoside salidroside have been extensively studied in Russia since they were first discovered in the 1960s [32–34]. The adaptogenic properties of R. rosea and salidroside have been well-documented [35–37] with the stimulant effect of these substances reported to play an important role [5, 33]. The extract SHR-5, manufactured by Swedish Herbal Institute, was characterised by HPLC-fingerprint analysis and standardised on the p-tyrosol-glucoside salidroside [30]. Olsson and colleagues [38] reported that the SHR-5 extract is standardised for rhodioloside (4 mg per 144 mg tablet) and appears to be a 70 % ethanolic extract with a 4:1 drug:extract ratio.

Evidence suggests that R. rosea inhibits monoamine oxidase and catechol-O-methyltransferase activity, thus modulating brain levels of monoamines, including serotonin and dopamine [39, 40]. Brain levels of these neurotransmitters may also be enhanced through increased permeability of the blood–brain barrier to their precursors [5]. Additionally, there is some evidence that R. rosea may affect the opioid system [41], and effects on cortisol secretion and HPA axis regulation and mediation of kinase enzymes have also been reported in the literature [29].

Much of the research on the adaptogenic effects of R. rosea is unavailable for review due to its publication in Russia; however, the available literature suggests that R. rosea increases resistance to a wide variety of stressors: with R. rosea extracts found to protect against the harmful effects of oxygen, cold, radiation and heavy physical exercise as well as increasing working capacity, decreasing fatigue, improving learning and long-term memory, and regulating brain function in rodents [35, 42]. The majority of these studies investigated the effects of single-dose administration with significant acute effects seen within 1–2 h post-dose; however, Petkov and colleagues [35] demonstrated improved memory using a maze model 24 h post-dose, as well as long-term memory of this maze after 10 days’ treatment.

In human studies a protective effect of R. rosea against the detrimental effects of stress and anxiety has similarly been demonstrated. In a review of the acute effects of adaptogens conducted by Panossian and Wagner [43] R. rosea was reported to be the most active of the adaptogens discussed, with evidence produced to demonstrate its stimulant effects.The standardised SHR-5 extract was used by Shevtsov and colleagues [30] in an RCT investigating the acute effects of R. rosea on capacity for mental work. Stressed and fatigued military cadets were administered either two (370 mg R. rosea) or three capsules (555 mg R. rosea), with both doses found to significantly reduce fatigue, as reflected in an anti-fatigue index based on performance of a variety of mental tasks. Beneficial effects on pulse pressure were also reported.

In a larger crossover RCT, Darbinyan and colleagues [5] investigated the effect of repeated low-dose R. rosea treatment on work-related fatigue. Fifty-six young, healthy physicians were assigned to receive 170 mg SHR-5 or placebo for 2 weeks in a crossover design, with an intermediate washout period of 2 weeks. The Fatigue Index was found to be significantly improved after 2 weeks’ R. rosea treatment compared with placebo, suggesting that R. rosea can be useful in reducing fatigue in stressful work situations. However, closer examination revealed that this effect was only significant when the night duty was shorter. When participants had longer night shifts, the dose administered was not sufficient to reduce fatigue. Future studies could aim to investigate the doses necessary for effects in situations of higher levels of fatigue and stress.

In addition to the anti-fatigue effects in non-clinical samples, chronic effects of R. rosea have also been demonstrated in patients with Generalised Anxiety Disorder (GAD). In a small open-label study, ten GAD patients received 170 mg R. rosea in the form of standardised SHR-5 tablets twice daily for 10 weeks [44]. A significant reduction in anxiety following this intervention was found on the Hamilton Anxiety Rating Scale (HARS) and the anxiety subscale of the Four Dimensional Anxiety and Depression Scale. Four participants were classed as achieving remission, defined as a score of ≤8 on the HARS and a score of 1 or 2 on Clinical Global Impressions of Improvement (CGI-I). Half the sample had ≥50 % reduction in scores on the HAM-A scale, suggesting clinical as well as statistical significance. However, the lack of placebo control in this study, as well as the small sample size, makes it difficult to draw firm conclusions about the efficacy of this extract in GAD.

The most common side effects of R. rosea involves irritability and insomnia [44], suggesting a possible stimulating effect. It has therefore been recommended that this extract not be used in patients with bipolar disorder [45]. In addition, there may be inhibitory effects on CYP3A4 and p-glycoprotein that should be considered [46]. Inhibition of these proteins affects drug metabolism and can lead to increased bioavailability of drugs; therefore, potential interactions should be examined prior to commencing R. rosea supplementation. On the other hand, general daily dose recommendations are in the range of 300–600 mg, with no known interactions with other drugs or herbs [27]. Repeated administration is thought to be safe, with no adverse events reported following 2 weeks’ treatment with 170 mg R. rosea [5].

The main biologically active components of C. asiatica are saponins (also called triterpenoids), which include asiaticosides amongst others [50]. A pharmacokinetic study of total triterpenoid fraction of Centella asiatica (TTFCA) suggests that the active compounds are well-absorbed in humans [51]. Peak plasma levels of Asiatic acid were reached 4.5 and 4.2 h following oral administration of 30 mg and 60 mg of extract, respectively. Plasma half-lives were 2.2 h in the 30 mg dose and 3.4 h in the 60 mg dose. Saponin levels were not detectable after 24 h post-dose. Repeated treatment over 7 days resulted in higher peak plasma concentrations, longer half-lives and greater area-under-the-curve absorption values [51].

With regard to anxiolytic effects, the main constituent of C. asiatica is the triterpineglycoside asiaticoside, as demonstrated in both in vitro and in vivo studies [49, 52]. Triterpines in C. asiatica increase serotonin, noradrenaline and dopamine in the brain, as well as reduce serum corticosterone levels [52]. It is thought that this is the mechanism through which C. asiatica has calming effects. It has also been postulated that C. asiatica may exert anxiolytic effects through increased GABA activity. An ethanolic extract was shown to increase GABA levels in mice [53], whilst an aqueous extract stimulated Glutamic Acid Decarboxylase (GAD) by over 40 % at a dose of 1 mg/mL in vitro [54]. Activity at the GABA_A receptor has also been demonstrated [55]. In addition, the anxiolytic activity may be in part due to binding to cholecystokinin receptors [56].

Anti-stress and anxiolytic effects of C. asiatica have been demonstrated using animal models. Long-term pretreatment resulted in enhanced elevated plus maze (EPM) performance and attenuated acoustic startle response (ASR), whilst gastric ulceration induced by cold and restraint stress was significantly inhibited [53]. The isolated compound asiaticoside has also been found to have anxiolytic effects at various doses [57]. However, it has been proposed that the method by which active compounds are extracted may affect the efficacy of this plant as an anxiolytic. In one study in rats only the methanol and ethyl acetate extracts, along with isolated asiaticoside, showed anxiolytic effects when using the EPM for 5 min [49]. Importantly, asiaticoside did not affect locomotor activity, suggesting that these compounds are without sedative effects in rodents. Using a rat model to determine whether the triterpenoid Asiatic Acid (AA) had anxiolytic effects, Ceremuga and colleagues [55] found that rats treated with AA spent more time in the open arms of the EPM, although the difference was non-significant. When administered with the benzodiazepine midazolam the effect reached statistical significance, which the authors attributed to a synergistic effect.

Evidence regarding anxiolytic effects of C. asiatica is somewhat scarce, although research interest has increased in recent years. In a systematic review, Ernst [58] found one study of C. asiatica that met search criteria. It was therefore stated that only preliminary data are available for this herb. Similarly, in a review including case reports, open-label and placebo-controlled trials, Baek and colleagues [45] reported that there is a scarcity of scientific evidence for the use of C. asiatica in the treatment of anxiety and insomnia. However, positive effects of C. asiatica on anxiety and general well-being have been demonstrated in a select number of human trials, providing a basis for further research.

In a small, double-blind RCT investigating acute effects on the acoustic startle response (ASR), 40 healthy participants were randomised to receive either 12 g C. asiatica or placebo. After 30 and 60 min, ASR amplitude was found to be significantly decreased for C. asiatica compared to placebo, although changes to self-rated anxiety were non-significant [48]. Considering that such a large dose of C. asiatica was administered, it is questionable as to whether this would be safe or effective long-term. Studies of the chronic effects of C. asiatica have used much lower doses, such as the 750 mg daily dose used by Wattanathorn and colleagues [59] who reported improved mood and cognitive function in an elderly population. However, in an RCT by Carlson and colleagues [60] which utilised only 68 mg C. asiatica in conjunction with Gingko biloba and fish oil, no treatment effect was reported in relation to overall Quality of Life (SF-36) scores in healthy older participants. It should be noted, however, that high baseline scores on the SF-36 were reported for participants in this study, suggesting that improvements may be range-limited.

With regard to clinical studies of C. asiatica, one open-label study was found with 33 participants diagnosed with Generalised Anxiety Disorder (GAD). C. asiatica leaf extract 500 mg BID was administered for 8 weeks. At the end of the study period, anxiety was significantly reduced, and stress and depression ratings were also reduced, as measured using the SF-36, Hamilton’s Brief Psychiatric Rating Scale (BPRS) and the State-Trait Anxiety Inventory (STAI) [61].

The recommended adult daily dose of total triterpenoid fraction of Centella asiatica extracts standardised for asiaticoside, Asiatic acid and madecassic acid is 60–120 mg, and for crude herb the recommended daily dose is 0.5–6 g [63]. C. asiatica has been shown to be safe when administered in combination with Gingko Biloba and Docosahexanoic Acid (DHA). Participants receiving this combination formula experienced no significant differences from placebo in platelet function or experience of adverse events, and adverse events reported were minor [60]. However, some mild side effects have been reported in other trials, including skin reactions and gastrointestinal upset [45]. In addition, three cases of jaundice with elevated liver enzymes were reported in Argentina following C. asiatica consumption for 20–60 days [62], although the dosage and standardisation of the consumed extract is unknown, and the patients recovered on discontinuation. As there is limited knowledge regarding long-term safety of C. asiatica consumption or the safety during breastfeeding, it is recommended that use of C. asiatica should not exceed 6 weeks and that nursing mothers should refrain from using this herb [50].