The Effect of Ginger (Zingiber officinalis) and Artichoke (Cynara cardunculus) Extract Supplementation on Functional Dyspepsia: A Randomised, Double-Blind, and Placebo-Controlled Clinical Trial Attilio Giacosa,1Davide Guido,2Mario Grassi,2Antonella Riva,3Paolo Morazzoni,3Ezio Bombardelli,3Simone Perna,4Milena A. Faliva,4 and Mariangela Rondanelli4 1Department of Gastroenterology, Policlinico di Monza, 20900 Milan, Italy 2Section of Biostatistics, Neurophysiology and Psychiatry, Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy 3Research and Development Unit, Indena, 20139 Milan, Italy 4Section of Human Nutrition, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Azienda di Servizi alla Persona, 27100 Pavia, Italy
Discussion The main result of this study is that the supplementation with ginger and artichoke extracts is efficacious in the short-term treatment of FD. This effect appears to be statistically significant when compared to placebo. It is interesting to note that the efficacy appears quickly, that is, within 14 days, and afterwards it is maintained until the 28th day of intervention. The intervention group shows treatment efficacy in 86.2% of cases after 28 days of supplementation, with marked reduction of dyspepsia intensity (grades 2 + 3 of the considered scale) in 63.1% of the treated cases, while only 52.5% of the control group patients showed a positive effect of placebo and only 24.6% of the placebo treated patients had a marked reduction of symptoms (grades 2 and 3).
Our results show the advantage of the supplementation, as compared to placebo, with a significant amelioration of 0.85 units on the MCA severity scale (of range 0–3) at 14 days. This result is adjusted for baseline symptoms and typologies of dyspepsia, and it persists until the end of the study (28th day). On raw data, the percentage difference between the intervention product and placebo approached 34%. This therapeutic gain is greater than what has been observed in previous studies with antisecretory and gastrokinetic drugs , as well as with artichoke extracts : in all these cases the advantage was in the range of 15%. Therefore, it seems that the association between ginger and artichoke extracts may increase the treatment efficacy on FD as compared to what was observed with artichoke extract alone or with antisecretory and gastrokinetic drugs.
The mechanisms involved in the pathophysiology of FD are multifactorial. As a matter of fact, a number of potential abnormalities have been reported in patients with FD including impaired fundic accommodation, gastric hypersensitivity to distention, abnormal duodenojejunal motility, duodenal motor and sensory dysfunction, duodenal hypersensitivity to lipids or acid, and Helicobacter pylori infection . In the present study the highest prevalence of FD subtype was represented by dysmotility-like FD and unspecified FD, while ulcer-like FD was present in very few cases of both the intervention and placebo groups, as shown in Table 1. Therefore, a prevalence of symptoms related to motility disorders was observed in the recruited patients. Most studies in animals have demonstrated that ginger root extracts increase gastric emptying and gastrointestinal transit . Micklefield et al. demonstrated a significant increase of the interdigestive motility after intervention with ginger extracts and Wu et al. showed that ginger accelerates gastric emptying and stimulates antral contractions in healthy volunteers [11, 26]. Animal emesis models likewise have shown reduced emesis with the administration of ginger. Gingerols and shogaols seem to be the active components .
Nausea, vomiting, and hypomotility involve a temporary dysfunction of the complex integrated network of cholinergic M3 and serotonergic 5-HT3/5-HT4 receptors. In this respect, major chemical constituents of the ginger roots lipophilic extracts such as -gingerol, -gingerol,  -gingerol, and -shogaol have been shown in several experimental models to modulate with a differentiated potency all these receptors. In particular, the capacity of ginger to reduce nausea and eventually vomiting seems to correlate with the effectiveness of these active ingredients to weakly inhibit M3 and 5-HT3 receptors. On the contrary, 5-HT4 receptors, which also play a role in gastroduodenal motility, do not seem to be involved in the effects of these compounds [11, 12].
Artichoke leaf extracts (ALE) have been used since long time, in traditional medicine, to treat dyspepsia and in 2003 Holtmann et al.  confirmed this effect in patients with FD. ALE increase bile flow and exert hepatoprotective , serum cholesterol lowering , and antioxidant and antispasmodic effects [30–32]. The bitter compounds of ALE and particularly cynaropicrin are responsible for the digestive beneficial effects [33, 34]. Holtmann et al.  showed that ALE were significantly better than placebo in reducing symptoms and improving the disease-specific quality of life in patients with functional dyspepsia. Anyhow the present study shows that the association of ginger extracts and ALE increases the efficacy on functional dyspepsia treatment with a 16.9% advantage as compared to the data found by Holtmann et al.  with ALE alone.
Of great interest appears the evaluation of the effect of ginger and artichoke supplementation on specific symptoms of functional dyspepsia. In this study the intervention was associated with a reduction of severity of epigastric pain, epigastric fullness, nausea, bloating, and early satiety: this decrease appears statistically significant for nausea and epigastric pain, over the observation time of 28 days. The only symptom which did not change was vomiting. On the contrary, in the placebo group, the statistical analysis shows that all symptoms have an increasing slope, which means an increase of symptom intensity with a statistically significant worsening for vomiting.
Considering the entity of the efficacy on the secondary outcomes, the supplementation shows a greatest efficacy on nausea, followed by a positive effect on epigastric fullness, epigastric pain, and bloating, after statistical adjustment for type of dyspepsia. The effect on nausea and on epigastric fullness could mainly be due to the ginger component and to its activity on gastric motility: this confirms what was previously observed in other clinical settings such as in nausea associated with pregnancy, chemotherapy, and motion sickness [12,35–37].
The effects on bile secretion that have been found in previous trials with artichoke extracts  may partially contribute to our results. The increase in bile acid secretion, observed after supplementation with ALE, is suitable to accelerate gastrointestinal transit and thus may alleviate bloating and fullness. The well-known antispasmodic feature of ALE may also increase both effects .
The treatment with the ginger and ALE supplement used in this study did not show any relevant side effect. This observation is of great importance when compared with the critical role of traditional prokinetic drugs such as domperidone, levosulpiride, or metoclopramide, frequently used in FD therapy. The treatment with these drugs is frequently associated with neurologic or endocrinologic side effects . In addition to this, a severe warning has been reported for domperidone treatment due to the sudden risk of cardiac death observed at doses of more than 30 mg per day in the elderly [40–43].
In conclusion, the association between ginger and artichoke leaf extracts appears efficacious in the treatment of functional dyspepsia and could represent a promising and safe treatment strategy for this frequent disease, even though additional studies are needed to confirm these results.