Complementary medicines and ginseng for inflammatory bowel disease-rooted in science, but will it bear fruit?

Table 1 Randomized controlled trials on complementary and alternative therapies in inflammatory bowel disease

	Population, n	Interventions	Findings	Comments	Ref.
Ginseng	UC patients with mild or moderate lesions within 15 cm of the anal verge, n = 120	Intervention: High dose suppository preparation of Panax notoginseng combined with other herbs; control: Low dose suppository preparation of Panax notoginseng combined with other herbs	Lower clinical symptom scores; improved clinical efficacy; lower IL-6 and IL-23; improved endoscopic scores; lower recurrence rate	Unclear blinding of proceduralists/investigators; clinical efficacy based on author’s criteria of clinical efficacy; no definition of recurrence; no significant difference in adverse reaction rate	Zeng et al[38], 2022
Cannabinoids	UC patients with Mayo ≥ 4 and ≤ 10, n = 32	Intervention: CBD rich cannabis (160 mg/mL CBD, 40 mg/mL THC), n = 17; control: Placebo oil, n = 15	Improved QoL; no difference in endoscopic scores or inflammatory markers	Gradual treatment dose escalation; intervention was well tolerated	Naftali et al[46], 2021
	UC patients with Mayo ≥ 4 and ≤ 10, n = 60	Intervention: CBD-rich extract capsules (50-250 mg twice a day), n = 29; control: Placebo capsules, n = 31	No significant difference in rates of remission; trend toward improved PGAS in PP analysis (82% had mild to normal disease at the end of treatment in the CBD-rich extract group vs 52% in the placebo group, P = 0.069; improved QoL	Disproportionate number of withdrawals and lower adherence in the CBD-rich extract group	Irving et al[45], 2018
	CD patients with CDAI 200-450, n = 20	Intervention: Cannabidiol oil (10 mg twice a day), n = 10; control: Placebo oil, n = 10	No significant improvement in CDAI or laboratory tests	Intervention had good tolerability and safety profile	Naftali et al[44], 2017
	Treatment refractory CD with CDAI > 200, n = 21	Intervention: THC cigarettes (115 mg), n = 11; control: Placebo cigarettes, n = 10	Greater improvements in CDAI scores (90% in the cannabis group versus 40% in the placebo group, P = 0.028); improved appetite and sleep; no significant difference in rates of remission	No significant side effects observed	Naftali et al[43], 2013
Curcumin	Quiescent UC, n = 89	Intervention: Curcumin (2 g/day) + 5-ASA, n = 45); control: Placebo + 5-ASA, n = 44	Reduced relapse rates in curcumin group (4.65% vs 20.51%, P = 0.049); improved clinical and endoscopic scores	Intervention was well tolerated	Hanai et al[47], 2006
	Active mild-to-moderate distal UC, n = 45	Intervention: Curcumin enema (140 mg daily) + oral 5-ASA, n = 23; control: Placebo + 5-ASA, n = 22	Improved clinical remission rate (71.4% vs 31.3%, P = 0.03) and endoscopic scores (85.7% vs 50%, P = 0.04) on PP analysis; no significant difference in treatment response, clinical remission or endoscopic scores on ITT analysis	Nearly 40% of patients in the curcumin group and 28% or patients in the placebo group did not complete the study period; no serious side effects observed	Singla et al[48], 2014
	Active mild-to-moderate UC refractory to mesalamine treatment, n = 50	Intervention: Curcumin capsules (3 g/day) + continue mesalamine, n = 26; control: Placebo capsules + continue mesalamine, n = 24	Improved rates of clinical remission (53.8% in the curcumin group vs 0% in the placebo group, P = 0.01), clinical response (65.3% vs 12.5%, P < 0.001) and endoscopic remission (38% vs 0%, P = 0.043)	No adverse effects observed	Lang et al[49], 2015
	Active mild-to-moderate UC, n = 62	Intervention: Curcumin capsules (150 mg three times a day) + mesalamine, n = 29; control: Placebo capsules + mesalamine, n = 33	There was no significant difference between curcumin and placebo in rates of clinical remission, clinical response, mucosal healing, and treatment failure	High attrition rate, 21 out of 62 patients (13/29 patients randomized to curcumin arm and 8/25 patients randomized to the placebo arm) did not complete the trial; no adverse clinical or biochemical effects were observed	Kedia et al[50], 2017
Ginger	Active mild-to-moderate UC, n = 46	Intervention: Dried ginger powder capsules (2000 mg/day), n = 22; control: Placebo capsules, n = 24	Improved SCCAIQ (7.6 ± 4.03 to 4.01 ± 1.23 in the ginger group vs 6.2 ± 3.22 to 5.55 ± 2.39, between group P < 0.017; improved stool frequency score (P = 0.041) and bowel distress and cramp scores (P = 0.029)	Minor adverse effects (heartburn)	Nikkhah-Bodaghi et al[53], 2019
Resveratrol	Active mild-to-moderate UC, n = 50	Intervention: Resveratrol capsules (500 mg daily), n = 25; control: Placebo capsules (containing MCT oil), n = 25	Increased QoL scores in resveratrol group vs placebo (P ≤ 0.001); significant reduction in CRP, TNF-α levels, and NF-κB levels in the resveratrol group (P ≤ 0.01); no significant change in the placebo group	Reported significant reduction in SCCAIQ scores in resveratrol group vs placebo; within group P values comparing baseline to post-intervention measurements were not provided	Samsami-Kor et al[54], 2015
	Active mild-to-moderate UC, n = 56	Intervention: Resveratrol capsules (500 mg daily), n = 28; control: Placebo capsules (containing MCT oil), n = 28	Increased QoL scores in resveratrol group following intervention (P < 0.01) and compared to placebo (P < 0.001); significant reduction in MDA, superoxide dysmutase and TAC following intervention (P < 0.001) and compared to placebo (P < 0.001)	Reported significant reduction in SCCAIQ scores in resveratrol group vs placebo; within group P values comparing baseline to post-intervention measurements were not provided	Samsamikor et al[55], 2016
Artemisia absinthium	CD patients with CDAI > 200, n = 20	Intervention: Dried powdered wormwood capsules (3 × 750 mg three times a day), n = 10; control: Placebo (unspecified form)	Improved rates of clinical response (P = 0.05); the authors reported a significant decrease in serum TNF-α levels; however, P value was recorded as 0.5	No “out of line” side effects reported that could be attributed to wormwood administration as per the authors	Krebs et al[51], 2010
	CD patients with CDAI ≥ 170, n = 40	Intervention: Wormwood powder capsules (2 × 250 mg three times a day; capsules also contained rose, cardamom, mastic resin), n = 20; control: Placebo capsules, n = 20	Reduced occurrence of CD exacerbation during steroid wean (P value not reported) and higher rates of clinical symptom score improvement in wormwood group compared to placebo (P = 0.01); 10% in wormwood group vs 80% in placebo required steroid re-commencement (P value not reported)	Adverse events not reported by authors	Omer et al[52], 2007
IN	UC patients with Mayo ≥ 6, n = 86	Intervention: Powdered IN capsules (0.5 g daily, n = 23), (1.0 g daily, n = 20), (2.0 g daily, n = 21); control: Placebo capsules, n = 22	Dose dependent significant improvement in clinical response in IN group, 13.6% to placebo, 69.6% to 0.5 g IN (P = 0.0002), 75.0% to 1.0 g IN (P = 0001) and 81.0% to 2.0 g IN (P < 0.0001); significantly improved rates of clinical remission with 1.0 g IN (55%, P = 0.0004) and 2.0 g IN (38.1%, P = 0.0093) compared to placebo (4.5%); improved rate of mucosal healing compared to placebo; significant decrease in partial Mayo scores, increase in serum albumin	Proportions of treatment-related adverse effects were 14% in placebo, 26% in 0.5 g IN, 35% in 1.0 g IN, and 29% in 2.0 g IN; adverse effects included liver dysfunction affecting 10%-20% of patients receiving IN; the study was terminated early due to safety concerns regarding IN (external to the trial)	Naganuma et al[57], 2018
	Active mild-to-moderate UC with Lichtiger index 5-10 intolerant or refractory to existing treatments, n = 42	Intervention: IN capsules (500 mg twice a day), n = 23; control: Placebo capsules, n = 19	Significant clinical response (P = 0.001) in the IN group but not in placebo; higher rate of clinical response (26.3% in the placebo group vs 82.6% in the IN group, P = 0.0003); significant improvement in serum albumin in IN group	Significantly higher baseline mean Lichtiger index in the IN group compared to the placebo group (9.04 ± 1.92 vs 7.47 ± 1.43, P = 0.0053)	Uchiyama et al[59], 2020
Aloe vera	Active mild-to-moderate UC with SCCAI ≥ 3, n = 44	Intervention: Oral Aloe vera gel (100 ml twice a day), n = 30; control: Placebo liquid preparation containing flavoring but no active agents, n = 14	Small but statistically significant fall in median SCCAI in the Aloe vera group (P = 0.01) but not in placebo; greater rate of clinical response (47% in Aloe vera group vs 14% in placebo group, OR = 5.3, P = 0.048; significant improvement in histological scores in Aloe vera group (P = 0.031) but not in placebo	Only minor adverse effects observed, which were similar in the Aloe vera and placebo groups	Langmead et al[60], 2004
Triticum aestivum	Active UC patients, n = 24	Intervention: Wheat grass juice (100 ml), n = 12; control: Placebo juice (similar to wheat grass in appearance but not in taste or smell), n = 12	Significantly differences in improvements in rectal bleeding (82% vs 58%, P = 0.025), DAI scores (91% vs 42%, P = 0.031), and PGAS (91% vs 42%, P = 0.031)	Blinding was limited but that inability to match the taste and smell of the control juice to wheat grass juice	Ben-Arye et al[61], 2002
Andrographis paniculata	Active mild-to-moderate UC, n = 120	Intervention: HMPL-004 (400 mg three times a day), n = 60; control: Mesalazine slow release granules (1500 mg three times a day), n = 60	Overall clinical efficacy (remission + partial remission + improvement) in 76% in the HMPL-004 group and 82% in the mesalazine group (P < 0.001 compared to baseline for both groups, no significant difference between groups; no between group differences in overall endoscopic efficacy or histological scores	Adverse reactions in the HMPL-004 group were rate and limited to mild allergic reactions or rash	Tang et al[63], 2011
	Active mild-to-moderate UC with Mayo Score 4-10, n = 223	Intervention: HMPL-004 capsules (1800 mg or 1200 mg per day in three divided doses), n = 74 in each intervention group; control: Placebo capsules, n = 75	Improved rates of clinical response with 1800 mg daily (60%, P = 0.0183) but not 1200 mg daily of HMPL-004 (45%, P = 0.5924) compared to placebo (40%); mucosal healing improved from baseline in 50% of patients receiving 1800 mg HMPL-004 and in 33.3% of patients receiving placebo (P = 0.0404)	Similar rate of adverse effects in the HMPL-004 groups and placebo	Sandborn et al[64], 2013
Tripterygium wilfordii	CD patients who had undergone terminal ileectomy, partial colectomy or ileocolectomy with ileocolonic anastomosis and CDAI ≤ 150 in the preceding 2 weeks, n = 39	Intervention: GTW tablets (1 mg/kg per day), n = 21; control: 5-ASA (4 g/day), n = 18	Lower rate of clinical recurrence (5.3% vs 23.5%, P < 0.001) and endoscopic recurrence (21.1% vs 52.9%, P < 0.001) in GTW group compared to 5-ASA group in PP analysis; higher proportion in endoscopic remission and lower proportion in endoscopic recurrence (P < 0.001) in the GTW group compared to 5-ASA group in PP analysis	Single-blinded; no severe adverse events occurred, and no patients were withdrawn prematurely from the study due to adverse events. The adverse event rate was similar between groups	Ren et al[65], 2013

UC: Ulcerative colitis; IL-6: Interleukin-6; IL-23: Interleukin-23; CBD: Cannabidiol; THC: Delta-9-tetrahydrocannabinol; QoL: Quality of life; PGAS: Patient global assessment of severity; CD: Crohn’s disease; CDAI: Crohn’s disease activity index; 5-ASA: 5-aminosalicylic acid; ITT: Intention-to-treat; SCCAIQ: Simple clinical colitis activity index questionnaire; MCT: Medium-chain triglycerides; CRP: C-reactive protein; TNF-α: Tumor necrosis factor-α; NF-κB: Nuclear factor-κB; MDA: Malondialdehyde; TAC: Total antioxidant capacity; IN: Indigo naturalis; OR: Odds ratio; DAI: Disease activity index; GTW: polyglycosides extracted from Tripterygium wilfordii; PP: Per protocol.

Table 2 The overlapping mechanisms of conventional inflammatory bowel disease therapies and complementary and alternative medicines

Mechanisms	Conventional therapies	Complementary and alternative medicines
NF-κB	Sulfasalazine, methotrexate, corticosteroids	Ginseng; curcumin; ginger; resveratrol; Indigo naturalis; Andrographis paniculata; Tripterygium wilfordii
JAK/STAT	JAK inhibitors	Alopolysaccharide (polymer from Aloe vera)
MAPK	Not targeted by current conventional therapies	Ginseng; ginger; Indigo naturalis
Intestinal epithelial barrier	Not targeted by current conventional therapies	Ginseng

NF-κB: Nuclear factor-κB; JAK: Janus kinase; STAT: Signal transducers and activator of transcription; MAPK: Mitogen-activated protein kinase.