The American Herbal Products Association (AHPA) regularly reviews scientific literature for new research that may be useful to the herbal products and dietary supplement industries. The following are some recent articles published in peer-reviewed journals.

A Placebo-Controlled, Pseudo-Randomized, Crossover Trial of Botanical Agents for Gulf War Illness: Curcumin (Curcuma longa), Boswellia (Boswellia serrata), and French Maritime Pine Bark (Pinus pinaster)
Gulf War Illness (GWI) is a chronic, multi-symptom condition of unknown etiology for which there are currently no FDA-approved treatments. The wide variety of symptoms experienced by those with GWI (i.e., pain, fatigue, cognitive dysfunction, gastrointestinal issues, respiratory difficulties, and dermatological complaints) have led some researchers to suggest that GWI is a neuroimmune condition involving systemic inflammation. Efforts are ongoing to rapidly screen potential treatments in order to prioritize agents for future efficacy testing.

As part of a larger investigation of nine botanicals, researchers conducted this study on three botanical extract preparations—turmeric, boswellia, and maritime pine—to identify promising anti-inflammatory botanicals for treatment of GWI symptoms. Each of the three botanical agents was tested in a lower-dosage and higher-dosage condition against both baseline and placebo. Participants completed 30 days of baseline symptom reports, followed by 30 days of placebo, 30 days of lower-dose botanical, and 30 days of higher-dose botanical. Data were analyzed using linear mixed models.

Turmeric reduced GWI symptom severity significantly more than placebo at both the lower (p < 0.0001) and higher (p = 0.0003) dosages. Boswellia was not more effective than placebo at reducing GWI symptoms at either the lower (p = 0.726) or higher (p = 0.869) dosages. Maritime pine was not more effective than placebo at the lower dosage (p = 0.954) but was more effective than placebo at the higher dosage (p = 0.006). All three botanicals were found to be well-tolerated at the tested dosages, and no clinically relevant adverse events attributed to the botanicals were observed. This trial has a small sample size so the results are preliminary, yet this study provides evidence that curcumin and maritime pine may help alleviate symptoms of GWI as authors found significant reduction in GWI symptom severity for both lower- and higher-dose turmeric, and for higher-dose maritime pine.

Int. J. Environ. Res. Public Health, March 2021
https://doi.org/10.3390/ijerph18052468

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Medicinal Mushrooms: Bioactive Compounds, Use, and Clinical Trials
Mushrooms have long been appreciated for their culinary and nutritional value and are increasingly used in dietary supplements and actively investigated for important health benefits and medicinal properties. Medicinal mushrooms have been shown to exhibit a variety of pharmacological activities, including antiallergic, antibacterial, antifungal, anti-inflammatory, antioxidative, antiviral, cytotoxic, immunomodulating, antidepressive, antihyperlipidemic, antidiabetic, digestive, hepatoprotective, neuroprotective, nephroprotective, osteoprotective, and hypotensive activities. In recent years, research into medicinal mushrooms has progressed exponentially, including clinical work and also efforts to identify and characterize mycochemicals and to define their actions and mechanisms. The bulk of research to date has focused on a few genera or species, for example reishi, shitake, and lion’s mane.

The authors of this comprehensive review highlighted the mechanisms of action by in vitro and preclinical scientific studies and indicated an urgent need to fully understand the individual and synergistic actions of fungal constituents. Suggestions for future studies included increased attention to in vivo dynamics and refining experimental design of in vivo and clinical studies. This review covers human clinical trials, in vitro and in vivo preclinical work, and provided a discussion of some of the best known and most studied bioactive metabolites of medicinal mushrooms.

Int. J. Mol. Sci., January 2021
https://doi.org/10.3390/ijms22020634

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Medicinal Seeds Ziziphus Spinosa for Insomnia: A Randomized, Placebo-Controlled, Cross-Over, Feasibility Clinical Trial
Insomnia is one of the most common sleep disorders, which can have a significant impact on many facets of mental and physical health. Pharmacotherapies primarily include benzodiazepines and sedating antidepressants which may be associated with side effects.
 
Ziziphus spinosa seeds (ZS) are commonly used in Chinese medicine, and are a potential candidate for the treatment of insomnia. An early mention of ZS use for sleep was published circa AD 992 in a classical Chinese herbal medicine book, Tai Ping Sheng Hui Fang. Clinical trials using ZS combined with other herbs have also shown promising effects on improving sleep quality and were safe for people with insomnia; to date there have been no rigorously designed, high quality studies of ZS as a stand-alone treatment for insomnia. This feasibility study aimed to explore trial design, eligibility criteria, recruitment, treatment acceptability, outcome measures, and provide data to perform a future full-scale randomized controlled trial of ZS for insomnia.

The researchers performed a randomized, double-blind, placebo controlled, cross-over trial of 12 participants with chronic insomnia over 14 weeks including a two-week run-in, four-weeks treatment with ZS or placebo, four-weeks wash out (no treatment given), and four-weeks treatment with the alternate treatment. Efficacy endpoints were only planned to provide preliminary results as the study was not appropriately powered to determine the efficacy of ZS for insomnia.

Yet, the outcomes showed encouraging results for the ZS treatment. Sleep quality measures and subjective sleep parameters such as total sleep time, sleep efficiency and sleep onset latency showed improvement after ZS but not placebo. This study takes the first steps toward evaluating a promising natural product with known sedative compounds that can be safely used by people with insomnia. The results of the trial support the feasibility and acceptability objectives of conducting a future fully powered randomized controlled trial of ZS for insomnia.

Complementary Therapies in Medicine, March 2021
https://doi.org/10.1016/j.ctim.2020.102657

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Effect of Cacao Polyphenol-Rich Chocolate on Postprandial Glycemia, Insulin, and Incretin Secretion in Healthy Participants
There is interest in the impact of dark chocolate on glycemic response, and the use of polyphenol-rich chocolate to prevent hyperglycemia after eating. In this stratified, randomized, crossover study, 48 healthy participants consumed either water (W) or cacao polyphenol-rich chocolate plus water (C) 15 minutes before a 50-g oral glucose tolerance test. Concentrations of blood glucose, insulin, free fatty acid, glucagon, and GLP-1 were evaluated before and at several timepoints after ingestion.

Peak plasma glucose concentrations did not differ significantly between groups W and C. However, plasma glucose concentrations at 120 minutes in group C were statistically significantly lower than those in group W (P < .01). Postprandial serum insulin, plasma GLP-1 concentrations, incremental serum insulin, and plasma GLP-1 area under the curve for group C were significantly higher than those for group W (P < .05). This study indicated that the intake of cacao polyphenol-rich chocolate could enhance early insulin and GLP-1 secretion in healthy participants and illustrates the potential of cacao polyphenol-rich chocolate in managing glucose levels.

Nutrition, May 2021
https://doi.org/10.1016/j.nut.2020.111128

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Impact of Silymarin in Individuals with Nonalcoholic Fatty Liver Disease: A Systematic Review & Meta-Analysis
Randomized clinical trials have been conducted examining the efficacy of silymarin in individuals with nonalcoholic fatty liver disease (NAFLD), with conflicting results. The authors in this meta-analysis evaluated the efficacy of silymarin in the treatment of NAFLD across trials by examining changes in liver biochemistry, body mass index, and liver histology. Silymarin treatment led to a statistically significant greater reduction in the levels of transaminases compared to placebo, irrespective of weight loss.

The meta-analysis concluded that silymarin seems to be effective in reducing transaminase levels in individuals with NAFLD. Despite the review and analysis showing beneficial effects of silymarin products, the analysis called attention to potential flaws related to the quality of the included studies, and noted that further well-designed studies should be carried out to examine whether this reduction in transaminase levels corresponds to histologic improvement.

Nutrition, March 2021
https://doi.org/10.1016/j.nut.2020.111092

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Effect of Green Tea Consumption in Treatment of Mild to Moderate Depression in Iranian Patients Living with HIV: A Double-Blind Randomized Clinical Trial
Depression occurs commonly in people living with HIV (PLWH) and when untreated can lead to lower compliance with antiretroviral drugs and poor control of infections. This study investigated the therapeutic anti-depressive effects of green tea extract (GTE) in PLWH receiving antiretroviral therapy. Fifty PLWH on antiretroviral therapy with a diagnosis of mild to moderate depression participated in a double-blind, placebo-controlled trial and underwent 12 weeks of treatment with either 400 mg GTE capsules or placebo twice daily.

The Hamilton depression scale of patients was measured before, 6 weeks, and 12 weeks after treatment in the two groups. The mean Hamilton scores showed a significant difference between the two groups after 12 weeks (P = 0.035). Repeated measures Analysis of Variance (ANOVA) test showed a significant effect for time × treatment interaction on the Hamilton mean score between the two groups (P = 0.000). The authors concluded that GTE can be considered as an alternative therapy for mild to moderate depression in PLWH.

Chinese Herbal Medicines, January 2021
https://doi.org/10.1016/j.chmed.2020.08.002

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The Effectiveness of Bacopa Monnieri as a Nootropic, Neuroprotective, or Antidepressant Supplement: Analysis of the Available Clinical Data
Bacopa monnieri, (Linn.) Wettst., is a plant with a long history in traditional medicine, used to enhance and improve memory and as an anxiolytic. The herb produces a vast number of active constituents including several alkaloids and saponins. Studies both in vitro and in vivo suggest neuroprotective and nootropic properties, and explore the respective mechanisms of action of B. monnieri against various neuronal insults.

This study reviewed B. monnieri’s efficacy as a neuroprotective drug and as a nootropic in healthy people and also against various neurological diseases including Alzheimer’s, dementia, depression, and anxiety. Two clinical studies showed statistically significant improvements in memory from older people who complained of memory loss. Some studies looked at B. monnieri to treat patients that had been selected based on criteria other than clinical diagnosis of depression or anxiety, which confounds analysis. Each of the clinical studies in healthy people measured an array of different neuropsychological tests, which makes meta-analysis challenging.

The authors reviewed preclinical and clinical trials, and suggested methods standardization and further larger extensive long-term studies against current standard drugs to determine whether B. monnieri is a viable alternative medicine.

Scientific Reports, January 2021
https://doi.org/10.1038/s41598-020-80045-2

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Beneficial Effects of Fish Oil and Cranberry Juice on Disease Activity and Inflammatory Biomarkers in Patients with Rheumatoid Arthritis
In patients with rheumatoid arthritis (RA) a prospective study was performed with fish oil supplementation alone or in combination with cranberry juice consumption, to determine if either treatment would ameliorate laboratory and clinical measurements of disease activity. 28-CRP modification of DAS28 (DAS28-CRP) and other inflammatory markers were analyzed in 62 RA patients. The first group was assigned to eat their typical diet, a second group was asked to consume 3 g of fish oil n-3 fatty acids daily, and a third group received both 3 g of fish oil n-3 fatty acids and 500 mL of reduced-energy cranberry juice daily.

The group receiving both fish oil and cranberry juice showed reduction in erythrocyte sedimentation rate (ESR, p=0.033), C-reactive protein (p=0.002), DAS28-CRP (p=0.001), adiponectin (p=0.021), and IL-6 levels (p=0.045), whereas the fish oil group only showed decreased levels in two measured markers, DAS28-CRP DAS28 (p=0.0261) and adiponectin (p=0.0239), compared to baseline values. The researchers concluded that the ingestion of cranberry juice adds beneficial effects to fish oil supplementation, decreasing disease activity and inflammatory biomarkers in RA patients.

Nutrition, January 2021
https://doi.org/10.1016/j.nut.2021.111183 

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About the Author: Holly E. Johnson PhD, is the chief science officer at the American Herbal Products Association (AHPA) where she is the primary scientific resource for the organization, providing individualized technical guidance to member organizations and helping the herbal industry use the latest science, technology and research to ensure consumers continue to have informed access to innovative, safe and effective herbal products. Dr. Johnson took her PhD in Pharmacognosy at the College of Pharmacy, University of Illinois – Chicago (UIC), under renowned Pharmacognosist and researcher Dr. Norman Farnsworth. She is currently a Research Associate with the National Tropical Botanical Garden and serves on AOAC Stakeholders Panels and Expert Review Panels for Foods and Dietary Supplements. She is a member of the USP Medical Cannabis Expert Panel, the Editorial Board of the AOAC International Journal, and also serves on the Advisory Boards of the American Botanical Council and the American Herbal Pharmacoepia. She can be reached at hjohnson@ahpa.org; 301-588-1171, ext. 103.