We are happy to provide you with this list of Clinical Studies that we have cited on our website. However, please note the following: 

Note:  All information on this website including these studies are for educational and  informational purposes only, and are not medical advice. Nothing on this website is intended to replace medical advice. It is important to consult with a healthcare professional before starting any new supplement regimen, especially if you have a medical condition, are taking medications,  if you are pregnant or nursing a baby.

Many of these ingredients have no known side effects or contraindications, however some of them may interfere with medications and may not be suitable for everyone.

These statements have not been evaluated by the Food and Drug Administration.
These products are not intended to diagnose, treat, cure or prevent any disease.

Anandamide Clinical Studies

The role of cannabinoids in adult neurogenesis Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543605/

Elevated Anandamide, Enhanced Recall of Fear Extinction, and Attenuated Stress Responses Following Inhibition of Fatty Acid Amide Hydrolase: A Randomized, Controlled Experimental Medicine Trial Link: https://www.sciencedirect.com/science/article/pii/S0006322319315896

The endocannabinoid system in humans: significant associations between anandamide, brain function during reward feedback and a personality measure of reward dependence Neuropsychopharmacology. (2021)  Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114914/

The endocannabinoid system as a target for the treatment of cannabis dependence Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2647947/

Endocannabinoid Anandamide Attenuates Acute Respiratory Distress Syndrome through Modulation of Microbiome in the Gut-Lung Axis Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699344/

The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC20983/

Effects of anandamide in migraine: data from an animal model Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072518/

 

Effect of endocannabinoid signalling on cell fate: life, death, differentiation and proliferation of brain cells Link: https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.14369

Anandamide and other N-acylethanolamines: A class of signaling lipids with therapeutic opportunities Link: https://www.sciencedirect.com/science/article/pii/S0163782722000492?via%3Dihub

Andrographis Clinical Studies

Andrographis and Respiratory Health 

  1. “A Double Blind, Randomized, Placebo Controlled Clinical Study to Evaluate the Efficacy and Safety of Andrographis paniculata Fixed Combination Kan Jang in the Treatment of Acute Upper Respiratory Tract Infections Including Sinusitis” Link: https://pubmed.ncbi.nlm.nih.gov/12487322/

  2. “Efficacy and safety of Andrographis paniculata in the treatment of uncomplicated upper respiratory tract infection: systematic review and meta-analysis” Link: https://pubmed.ncbi.nlm.nih.gov/15095142/

  3. “A randomized, controlled study on the efficacy of standardized Andrographis paniculata extract SHA-10 in patients with uncomplicated upper respiratory tract infection” Link: https://www.sciencedirect.com/science/article/abs/pii/S0944711309003201

  4. “A prospective, randomized, double-blind, placebo-controlled study of Andrographis paniculata fixed combination Kan Jang in the treatment of acute lower respiratory tract infections” Link: TBD

  5. “Andrographolide in the symptomatic treatment of uncomplicated upper respiratory tract infection: systematic review and meta-analysis” Link: https://pubmed.ncbi.nlm.nih.gov/14748896/

  6. Efficacy of Andrographis paniculata, Nees for pharyngotonsillitis in adults. -J Med Assoc Thai, 1991 Link: https://pubmed.ncbi.nlm.nih.gov/1797953/
  7. Pharmacokinetic and oral bioavailability of andrographolide from Andrographis paniculata fixed combination Kan Jang in rats and human. –Phytomedecine, 2000 Link: https://pubmed.ncbi.nlm.nih.gov/11081986/
  8.  Andrographis paniculata in the Treatment of Upper Respiratory Tract Infections: A Systematic Review of Safety and Efficacy. Planta Med 2004 Link: https://www.researchgate.net/publication/8608873_Andrographis_paniculata_in_the_Treatment_of_Upper_Respiratory_Tract_Infections_A_Systematic_Review_of_Safety_and_Efficacy
  9.  Andrographis paniculata in the symptomatic treatment of uncomplicated upper respiratory tract infection: systematic review of randomized controlled trials. – Journal of clinical pharmacy 2004
  10.  A randomized double-blind placebo controlled clinical evaluation of extract of Andrographis paniculata (KalmColdTM) in patients with uncomplicated upper respiratory tract infection. phytomedicine 2010 link: https://pubmed.ncbi.nlm.nih.gov/20092985/
  11.  Improving the efficacy of conventional therapy by adding andrographolide sulfonate in the treatment of severe hand, foot, and mouth disease: A randmoized controlled Trial. Evidence-based complementary and alternative Medicine, 2013 Link: https://pubmed.ncbi.nlm.nih.gov/23401711/
  12.  Andrographis paniculata (Chuān Xīn Li ́an) for symptomatic relief of acute respiratory tract infections in adults and children: A systematic review and meta-analysis. PLOS ONE, 2017 Link: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207713

Andrographis and Covid-19 

  1. https://pubmed.ncbi.nlm.nih.gov/37765004 Conclusions. Overall, the results of this study suggest that Kan Jang® is effective in treating mild and moderate COVID-19 irrespective of the SARS-CoV-2 variant of infection.
  2. https://pubmed.ncbi.nlm.nih.gov/35889352/ A. paniculata is apromising natural source for drug discovery regarding COVID-19 post-infectious treatment, rather than prophylaxis.
  3. Andrographolide as a potential inhibitor of SARS-CoV-2 main protease: an in silico approach. – J of Biomol structures and Dynamics, 2020
  4. Efficacy of Kan Jang® in Patients with Mild COVID-19: A Randomized, Quadruple-Blind, Placebo-Controlled Trial Link: https://www.mdpi.com/1424-8247/16/9/1196

Andrographis and Cancer 

  1. https://www.cghjournal.org/article/S1542-3565(15)00515-7/fulltext

    Investigation of the Combination Effects of Andrographis Paniculata With Chemotherapeutics for Esophageal Cancer Treatment

  2. https://pubmed.ncbi.nlm.nih.gov/35089340/

    A combined treatment with melatonin and andrographis promotes autophagy and anticancer activity in colorectal cancer

  3. https://pubmed.ncbi.nlm.nih.gov/35367343/

    Andrographolide suppresses non-small-cell lung cancer progression through induction of autophagy and antitumor immune response

Andrographis and Immune Health

  1. https://pubmed.ncbi.nlm.nih.gov/34376353/ Conclusion: Supplementation of SAPE resulted in immunomodulatory effects evidenced by its effects on immune cells and cytokines and it was found to be safe and tolerable.

Andrographis and Osteoarthritis 

  1. https://pubmed.ncbi.nlm.nih.gov/37354697/

    Identification of Andrographolide as a novel FABP4 inhibitor for osteoarthritis treatment

Andrographis and Rheumatoid Arthritis

  1. “Efficacy and safety of Andrographis paniculata (Nees) for the treatment of rheumatoid arthritis: clinical trial study” Link: https://pubmed.ncbi.nlm.nih.gov/19408036/

Berberine Clinical Studies

Berberine and Blood Sugar Management 

1. Efficacy of Berberine in Patients with Type 2 Diabetes- link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2410097/

2. Berberine Improves Insulin Sensitivity by Inhibiting Fat Store and Adjusting Adipokines Profile in Human Preadipocytes and Metabolic Syndrome Patients– Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310165/

3. Berberine Lowers Blood Glucose in Type 2 Diabetes Mellitus Patients through Increasing Insulin Receptor Expression – Metabolism (2010) Link: https://pubmed.ncbi.nlm.nih.gov/19800084/

4. Berberine, a Herbal Metabolite in the Metabolic Syndrome: The Risk Factors, Course, and Consequences of the Disease –  Molecules (2022)  Concludes that Berberine in Combination with Lifestyle Changes Improves Insulin Resistance and Lipid Profile in the Metabolic Syndrome – Link: https://www.mdpi.com/1420-3049/27/4/1351

5. Berberine in the Treatment of Type 2 Diabetes Mellitus: A Systemic Review and Meta-Analysis – Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478874/

6. Therapeutic effect of berberine on metabolic diseases: Both pharmacological data and clinical evidence – Science Direct (2021) Link: https://www.sciencedirect.com/science/article/pii/S0753332220311768

7. Glucose-lowering effect of berberine on type 2 diabetes: A systematic review and meta-analysis Frontiers in Pharmacology (2022) Link:  https://www.frontiersin.org/articles/10.3389/fphar.2022.1015045/full

8. Effect of berberine administration on metabolic syndrome, insulin sensitivity, and insulin secretion – Metab Syndrome Related Disorders (2013)   Conclusions: Administration of berberine leads to remission of metabolic syndrome and decreases in waist circumference, SBP, triglycerides, and total insulin secretion, with an increase in insulin sensitivity. https://pubmed.ncbi.nlm.nih.gov/23808999

9. Berberine inhibits hepatic gluconeogenesis via the LKB1-AMPK-TORC2 signaling pathway in streptozotocin-induced diabetic rats – World Journal of Gastroenterology (2015) Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491964/

10. Berberine Modulates Gut Microbiota and Reduces Insulin Resistance via the TLR4 Signaling Pathway – Experimental and Clinical Endocrinology & Diabetes (2018)  Link: https://www.researchgate.net/publication/322700144

11. Berberine improves insulin sensitivity by inhibiting fat store and adjusting adipokines profile in human preadipocytes and metabolic syndrome patients- Evid Based Complement Alternat Med (2012) Link: https://pubmed.ncbi.nlm.nih.gov/22474499/

12. The Effect of Berberine Supplementation on Glycemic Control and Inflammatory Biomarkers in Metabolic Disorders: An Umbrella Meta-Analysis of Randomized Controlled Trials – Clinical Therapeutics (2023) – Link: ://pubmed.ncbi.nlm.nih.gov/38016844/

13. The Effect of Berberine on Metabolic Profiles in Type 2 Diabetic Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials – Occidative Medicine and Cellular Longevity (2021)  Link: https://www.hindawi.com/journals/omcl/2021/2074610/

14. Alkaloids as Promising Agents for the Management of Insulin Resistance: A Review

15. Addressing the preventive and therapeutic perspective of berberine against diabetes

Conclusion: “In addition to diabetes, multiple studies have suggested the beneficial effects of berberine in other metabolic diseases such as cancer, obesity, non-alcoholic fatty liver diseases, hyperlipidemia, and gout. These reports collectively indicate that berberine is a potent oral hypoglycemic agent with modest effect on lipid metabolism. Berberine may serve a low-cost and new drug candidate for the management of diabetes.” 

16. The Effect of Berberine Supplementation on Glycemic Control and Inflammatory Biomarkers in Metabolic Disorders: An Umbrella Meta-Analysis of Randomized Controlled Trials

Berberine and Cholesterol Management 

1. Efficacy of Berberine in Patients with Non-Alcoholic Fatty Liver Disease – PLOS One (2015) Link: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0134172

2. Berberine ameliorates nonalcoholic fatty liver disease by a global modulation of hepatic mRNA and lncRNA expression profiles – Journal of Transl Med (2015) Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4316752/

3. Efficacy of Berberine Alone and in Combination for the Treatment of Hyperlipidemia: A Systematic Review, J. Evidence-based Compl. & Alt Medicine, 2017 Link: https://pubmed.ncbi.nlm.nih.gov/29228784/

4. Meta-analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension, J. of Ethnopharmacology (2015) Link: https://pubmed.ncbi.nlm.nih.gov/25498346/

5. Efficacy and Safety of Berberine Alone or Combined with Statins for the Treatment of Hyperlipidemia: A Systematic Review – J Evid Based Complementary Altern Med  (2017) Link: https://journals.sagepub.com/doi/10.1177/2156587216687695

6. The Therapeutic Effect of Berberine in the Treatment of Nonalcoholic Fatty Liver Disease: A Meta-Analysis – Journal of  Evidence-Based Complementary and Alternative Medicine (2016) Link: https://www.hindawi.com/journals/ecam/2016/3593951/

Berberine and Heart Health

1. Berberine on the Prevention and Management of Cardiometabolic Disease: Clinical Applications and Mechanisms of Action – Amer Journal of Chinese Medicine (2021) Link: https://pubmed.ncbi.nlm.nih.gov/34488551/

2. The effects of berberine supplementation on cardiovascular risk factors in adults: A systematic review and dose-response meta-analysis – Frontiers in Nutrition (2022) Link: https://www.frontiersin.org/articles/10.3389/fnut.2022.1013055/full

3. Berberine in Cardiovascular and Metabolic Diseases: From Mechanisms to Therapeutics  – Theranostics (2019) Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485276/

4. A New Therapeutic Candidate for Cardiovascular Diseases: Berberine –Front Pharmacol  (2021) Link:  https://www.frontiersin.org/articles/10.3389/fphar.2021.631100/full

5. Effect of Berberine on C-reactive protein: A systematic review and meta- analysis of randomized controlled trials – Complementary Therapies in Medicine (2019) Link: https://www.sciencedirect.com/science/article/abs/pii/S0965229919308179?via%3Dihub

Berberine and Mood Enhancement

1. On the mechanism of antidepressant-like action of berberine chloride European Journal of Pharmacology (2008) Link: https://www.sciencedirect.com/science/article/abs/pii/S0014299908005694?via%3Dihub

2. Regulation of the kynurenine/serotonin pathway by berberine and the underlying effect in the hippocampus of the chronic unpredictable mild stress mice –  Behavioural Brain Research (2022) Link: https://www.sciencedirect.com/science/article/abs/pii/S0166432822000328

3. Berberine alleviates symptoms of anxiety by enhancing dopamine expression in rats with post-traumatic stress disorder – Korean J Physiol Pharmacol (2018)  Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840077/

4. Pharmacological effects of berberine on mood disorders – Journal of Cellular and Molecular Medicine (2018)  Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307759/

5. Berberine attenuates depressive-like behaviors by suppressing neuro-inflammation in stressed mice – Brain Research Bulletin (2017) Link: https://pubmed.ncbi.nlm.nih.gov/28842306/

6. Current Evidence and Future Directions of Berberine Intervention in Depression – Frontiers in Pharmacology (2022) Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9168319/

Note of Interest: LEO-HB Technology has overcome this obstacle noted in this study:

“Although berberine has been researched for many years and received positive therapeutic feedback in an animal model of depression, there is poor bioavailability of oral or parenteral administration due to low absorption and intestinal first-pass effect, restricting its utilization in the treatment of depression (Fan et al., 2019). Therefore, it is necessary to overcome the problem of bioavailability and improve its therapeutic effects before it can be applied to clinical treatment.”

 

Berberine and Other Conditions 

1. Berberine: A Promising Treatment for Neurodegenerative Diseases – Frontiers in Pharmacology (2022)  Link: https://www.frontiersin.org/articles/10.3389/fphar.2022.845591/full

2. Effects of berberine on β-secretase activity in a rabbit model of Alzheimer’s disease Arch Med Sci (2013) Link: https://pubmed.ncbi.nlm.nih.gov/23516061/

3. Berberine ameliorates β-amyloid pathology, gliosis, and cognitive impairment in an Alzheimer’s disease transgenic mouse model – Neurobiol Aging (2012) Link: https://pubmed.ncbi.nlm.nih.gov/22459600/

4. Berberine for the treatment of hypertension: A systematic reviewComplement Ther Clin Pract. (2021)

5. Berberine improves negative symptoms and cognitive function in patients with chronic schizophrenia via anti-inflammatory effect: a randomized clinical trialChin Med. (2023)

6. Berberine as a Potential Anticancer Agent: A Comprehensive ReviewMolecules. (2021)

 

Birch Clinical Studies

Potential benefits of birch supported by human clinical studies

1. Antimicrobial Activity and Wound-Healing Capacity of Birch, Beech and Larch Bark Extracts Molecules  (2022) Link: https://pubmed.ncbi.nlm.nih.gov/35566174/

2. From a Traditional Medicinal Plant to a Rational Drug: Understanding the Clinically Proven Wound Healing Efficacy of Birch Bark Extract – Plos One (2014) Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3899119/

3. Anti-Inflammatory and Anticancer Properties of Birch Bark-Derived Betulin: Recent Developments – Plants (2021) Link: https://www.mdpi.com/2223-7747/10/12/2663

To Note: The Bioavailability factor in this study is overcome by LEO-HB® Technolgy without the use of artificial excipients, solvents and emulsifiers used in nanotechnology which may cause discomfort or harm to the digestive tract:

“It is expected that by overcoming the low bioavailability of betulin by encapsulating it into nanocarriers, this promising natural compound may provide novel possibilities for targeting inflammation-related cancers.”

4. Betulin attenuates lung and liver injuries in sepsis – International Immunopharmacology (2016) Link: https://www.sciencedirect.com/science/article/abs/pii/S1567576915301971?via%3Dihub

5. Biological activity of the birch leaf and bark (2022)  https://scindeks-clanci.ceon.rs/data/pdf/0455-6224/2022/0455-62242242089D.pdf

6. An aqueous birch leaf extract of Betula pendula inhibits the growth and cell division of inflammatory lymphocytes – Journal of Ethnopharmacology (2011) Link: https://www.sciencedirect.com/science/article/abs/pii/S0378874111003540?via%3Dihub

Birch and Blood Sugar Management

An overview on the role of bioactive α-glucosidase inhibitors in ameliorating diabetic complications – Food and Chemical Toxicity (2020) Link: https://www.sciencedirect.com/science/article/pii/S0278691520306281?via%3Dihub

Inhibition of SREBP by a Small Molecule, Betulin, Improves Hyperlipidemia and Insulin Resistance and Reduces Atherosclerotic Plaques – Cell Metabolism (2011)  https://www.cell.com/cell-metabolism/fulltext/S1550-4131(10)00446-8?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1550413110004468%3Fshowall%3Dtrue   

Boswellia Clinical Studies

Boswellia and  Pain Management, Osteoarthritis, Joint Health

1. A randomized, double blind, placebo controlled, cross over study to evaluate the analgesic activity of Boswellia serrata in healthy volunteers using mechanical pain model – India Journal of Pharmacology (2014) Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175880/

2. Efficacy and safety of Boswellia serrata extract in the treatment of osteoarthritis: a systematic review and meta-analysis – BMC Complementary Medical Therapy (2020) Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368679/

3. “Efficacy and safety of a standardized Boswellia serrata extract in the management of osteoarthritis: a randomized, double-blind, placebo-controlled, crossover trial” (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3309643/)

4. Boswellia serrata extract for the treatment of collagenous colitis: a double-blind, randomized, placebo-controlled trial –International Journal of Colorectal Disease (2007)

5. Clinical evaluation of Boswellia serrata (Shallaki) resin in the management of Sandhivata (osteoarthritis) – AYU (2011) Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3361921/

6. Comparative efficacy and tolerability of 5-Loxin and Aflapin against osteoarthritis of the knee: a double blind, randomized, placebo controlled clinical study –  Int J Med Sci (2010) Link: https://pubmed.ncbi.nlm.nih.gov/21060724/

7. Special extract of BOSWELLIA serrata (H 15)* in the treatment of rheumatoid arthritis Phytomedicine Vol. 3 (1), pp. 91-94,1996

8.  Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee – A randomized double blind placebo controlled trial Phytomedicine 10: 3–7 (2003)

9. Open, randomized, controlled clinical trial of Boswellia serrata extract as compared to valdecoxib in osteoarthritis of the knee Indian J Pharmacol, 2007

10.  A double blind, randomized, placebo controlled study of the efficacy and safety of 5-Loxin® for the treatment of osteoarthritis of the knee Arthritis Research & Therapy 2008, 10:R85

11.  A Double Blind, Randomized, Placebo Controlled Clinical Study Evaluates the Early Efficacy of Aflapin® in Subjects with Osteoarthritis of the knee Int. J. Med. Sci. 2011, 8

12. A randomized, double blind, placebo controlled, cross over study to evaluate the analgesic activity of Boswellia serrata in healthy volunteers using mechanical pain model Indian Journal of Pharmacology 2014

13. A pilot, randomized, double‐blind, placebo‐controlled trial to assess the safety and efficacy of a novel Boswellia serrata extract in the management of osteoarthritis of the knee Phytotherapy Research, 2019

14. Effectiveness of Boswellia and Boswellia extract for osteoarthritis patients: a systematic review and meta-analysis BMC 2020

15.https://todayspractitioner.com/wp-content/uploads/2023/06/BoswelliaResearchReview_BMCMedicineTherapies.pdf

16. https://todayspractitioner.com/wp-content/uploads/2023/06/Boswellia2011_InternationalJournalMedicalSciences.pdf

17. https://todayspractitioner.com/wp-content/uploads/2023/06/Boswellia2011_InternationalJournalMedicalSciences.pdf

18. Efficacy and safety of curcumin and its combination with boswellic acid in osteoarthritis: a comparative, randomized, double-blind, placebo-controlled study – BMC Complementary Alternative Medicine (2018)  Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761198/

 

Boswellia and Brain Health

1. Boswellic Acids Improve Clinical Cognitive Scores and Reduce Systemic Inflammation in Patients with Mild to Moderate Alzheimer’s Disease 

 

2. Boswellia serrata extract shows cognitive benefits in a double-blind, randomized, placebo-controlled pilot clinical trial in individuals who suffered traumatic brain injury – Brain Injury (2022) Link: https://www.tandfonline.com/doi/abs/10.1080/02699052.2022.2059816

Boswellia and Digestive Health

1. The gastric ulcer protective effect of boswellic acids, a leukotriene inhibitor from Boswellia serrata, in rats

2. Dietary Boswellia serrata Acid Alters the Gut Microbiome and Blood Metabolites in Experimental  Models– Nutrients (2022) link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8877038/

3. Boswellia serrata Preserves Intestinal Epithelial Barrier from Oxidative and Inflammatory Damage – Plos One (2015) Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425476/

4. Beneficial Effects on Abdominal Bloating with an Innovative Food-Grade Formulation of Curcuma longa and Boswellia serrata Extracts in Subjects with Irritable Bowel Syndrome and Small Bowel Dysbiosis – Nutrients (2022) Link: https://www.mdpi.com/2072-6643/14/3/416

Caryophyllene Clinical Studies

Caryophyllene and Sleep

1. Essential Oil from the Leaves of Chromolaena odorata, and Sesquiterpene Caryophyllene Oxide Induce Sedative Activity in Mice  Pharmaceuticals, (2021)

2. The anxiolytic-like effect of an essential oil derived from Spiranthera odoratissima A. St. Hil. leaves and its major component, β-caryophyllene, in male mice journal Neuropharmacology (2012) caryophyllene has anxiolytic effects in mice, which could be helpful for those who struggle with anxiety-related sleep disorders

 

Caryophyllene and Pain Management: 

β-Caryophyllene, a CB2-Receptor-Selective Phytocannabinoid, Suppresses Mechanical Allodynia in a Mouse Model of Antiretroviral-Induced Neuropathic Pain  – Molecules (2020)

β-Caryophyllene is a phytocannabinoid, which is a CB2-receptor-selective agonist []. It has been shown to reduce the expression of cytokines and attenuate mechanical allodynia in animal models of paclitaxel-induced neuropathic pain and diabetic neuropathic pain [,]. 

2. Evaluation of the terpenes β-caryophyllene, α-terpineol, and γ-terpinene in the mouse chronic constriction injury model of neuropathic pain: possible cannabinoid receptor involvement – Psychopharmacology (2022)

Polypharmacological Properties and Therapeutic Potential of β-Caryophyllene: A Dietary Phytocannabinoid of Pharmaceutical Promise – Current Pharm Des. (2016)

 

CBD Clinical Studies

CBD and Sleep and Anxiety:

1. Cannabidiol in Anxiety and Sleep: A Large Case Series

A 2019 study published in The Permanente Journal found that CBD improved sleep and anxiety in a small group of people with anxiety and sleep problems. The study involved 72 adults, and the participants experienced improved sleep scores within the first month of taking CBD:

  • Shannon, S., Lewis, N., Lee, H., & Hughes, S. (2019). Cannabidiol in Anxiety and Sleep: A Large Case Series. The Permanente Journal, 23, 18–041. doi: 10.7812/tpp/18-041

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326553/

2. Cannabidiol as a Potential Treatment for Anxiety Disorders

Preclinical evidence conclusively demonstrates CBD’s efficacy in reducing anxiety behaviors relevant to multiple disorders, including PTSD, GAD, PD, OCD, and SAD, with a notable lack of anxiogenic effects. CBD’s anxiolytic actions appear to depend upon CB1Rs and 5-HT1ARs in several brain regions; however, investigation of additional receptor actions may reveal further mechanisms. Human experimental findings support preclinical findings, and also suggest a lack of anxiogenic effects, minimal sedative effects, and an excellent safety profile.

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604171/

3. Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test

Results: Compared to placebo, pretreatment with 300 mg of CBD significantly reduced anxiety during the speech. No significant differences in VAMS scores were observed between groups receiving CBD 150 mg, 600 mg and placebo.

  • Linares, I. M., Zuardi, A. W., Pereira, L. C., Queiroz, R. H., Mechoulam, R., & Guimarães, F. S. (2018). Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test. Brazilian Journal of Psychiatry, 40(1), 9-14. doi: 10.1590/1516-4446-2017-0015

Link: https://pubmed.ncbi.nlm.nih.gov/30328956/

4. Cannabis, Cannabinoids, and Sleep: a Review of the Literature

A 2017 study published in Current Psychiatry Reports reviewed the existing research on CBD and sleep, and concluded that Preliminary research into cannabis and insomnia suggests that cannabidiol (CBD) may have therapeutic potential for the treatment of insomnia. In addition, the author noted CBD may hold promise for REM sleep behavior disorder and excessive daytime sleepiness, while nabilone may reduce nightmares associated with PTSD and may improve sleep among patients with chronic pain. 

  • Babson, K. A., Sottile, J., & Morabito, D. (2017). Cannabis, Cannabinoids, and Sleep: a Review of the Literature. Current Psychiatry Reports, 19(4), 23. doi: 10.1007/s11920-017-0775-9

Link: https://pubmed.ncbi.nlm.nih.gov/28349316/

5. Effects of acute systemic administration of cannabidiol on sleep-wake cycle in rats

Conclusion: The systemic acute administration of CBD appears to increase total sleep time, in addition to increasing sleep latency in the light period of the day of administration.

https://pubmed.ncbi.nlm.nih.gov/23343597/

CBD and Pain Management:

There have been several human clinical studies investigating the potential pain-relieving effects of CBD. Here are a few examples:

1. A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment

2020 randomized, double-blind, placebo-controlled trial published in the Journal of Clinical Medicine found that a topical CBD formulation reduced pain and improved physical function in people with peripheral neuropathy, a type of nerve damage that can cause pain and numbness in the extremities.

Link:  https://pubmed.ncbi.nlm.nih.gov/24420962/

2. Efficacy, Safety, and Regulation of Cannabidiol on Chronic Pain: A Systematic Review

A 2019 systematic review and meta-analysis published in the journal Frontiers in Neurology evaluated the efficacy of CBD for chronic pain management. The authors analyzed data from 11 randomized controlled trials and concluded that CBD may be effective for reducing chronic pain in adults.

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9288157/

3. A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis

A 2018 randomized, double-blind, placebo-controlled study published in the European Journal of Pain investigated the effects of CBD on chronic pain in people with multiple sclerosis. The study found that CBD reduced pain and improved sleep quality in the participants.

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222489/

4. Study on chronic pain: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922297/

5. Study on peripheral neuropathy: (link TBD) 

6. Study: Add-on Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex 

CBD and Neuroprotection

Title: “Cannabidiol, neuroprotection and neuropsychiatric disorders”

Published in: Science Direct (2016)

Link: https://www.sciencedirect.com/science/article/abs/pii/S1043661816000396?via%3Dihub

Title: “Cannabidiol Rescues Acute Hepatic Toxicity and Seizure Induced by Cocaine”

Published in: Mediators of Inflammation (2015)

Conclusion: While primarily addressing acute hepatic toxicity and seizures induced by cocaine, this trial incidentally explored CBD’s neuroprotective properties. The study concluded that CBD demonstrated a protective effect against both hepatic and neurological damage induced by cocaine, shedding light on its potential neuroprotective role.

Link: https://pubmed.ncbi.nlm.nih.gov/25999668/

Title: “Cannabinoids for treatment of Alzheimer’s disease: moving toward the clinic”

Published in: Frontiers in Pharmacology (2014) 

Link: https://www.frontiersin.org/articles/10.3389/fphar.2014.00037/full

CBD and Inflamation 

1. Cannabidiol as an Emergent Therapeutic Strategy for Lessening the Impact of Inflammation on Oxidative Stress

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085542/

 

2. Cannabidiol Attenuates Cisplatin-Induced Nephrotoxicity by Decreasing Oxidative/Nitrosative Stress, Inflammation, and Cell Death

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085542/

Anxiety and depression:

Epilepsy:

Addiction:

Skin conditions:

CLA Clinical Studies

CLA and Various Conditions Mentioned 

  1. The effects of conjugated linoleic acid supplementation on glycemic control, adipokines, cytokines, malondialdehyde and liver function enzymes in patients at risk of cardiovascular disease: a GRADE-assessed systematic review and dose–response meta-analysis – BMC Nutrition Journal (2023) Link: https://nutritionj.biomedcentral.com/articles/10.1186/s12937-023-00876-3

  2. “Conjugated linoleic acid supplementation for twelve weeks increases lean body mass in obese humans” (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826589/)

CoQ10 Clinical Studies

 

1. Clinical Evidence for Q10 Coenzyme Supplementation in Heart Failure: From Energetics to Functional Improvement – Journal of Clinical Medicine  (2020) 

2. Coenzyme Q10: Clinical Applications beyond Cardiovascular Diseases – Nutrients (2021) “Clinical evidence supports supplementation with high doses of bioavailable-CoQ10 (≥200 mg/day) to support heart health in patients affected by coronary heart disease and heart failure, partly modulating a number of risk factors for these conditions, and partly directly acting on myocardial cell metabolism.”

3. Ubiquinol supplementation enhances peak power production in trained athletes: a double-blind, placebo controlled study – Journal of the Society of International Sports Nutrition (2013) “daily supplementation of 300 mg Ubiquinol for 6 weeks significantly enhanced physical performance measured as maximum power output by +0.08 W/kg bw (+2.5%) versus placebo in young healthy trained German Olympic athletes.” 

4. Nutrient Therapy for the Improvement of Fatigue Symptoms – Nutrients (2023) 

5. Coenzyme Q10 supplementation – In ageing and disease – Mechanisms of Ageing and Development (2021) 

6. Effectiveness of Coenzyme Q10 Supplementation for Reducing Fatigue: A Systematic Review and Meta-Analysis of Randomized Controlled Trials – Frontiers in Pharmacology (2022) 

7. The effect of dietary intake of coenzyme Q10 on skin parameters and condition: Results of a randomised, placebo-controlled, double-blind study

 

Gotu kola Clinical Studies

Gotu Kola and Skin Health

1. Pharmacological Effects of Centella asiatica on Skin Diseases: Evidence and Possible Mechanisms – Evidence Based Complimentary Alternative Med (2021) 

2.Pharmacological Effects of Centella asiatica on Skin Diseases: Evidence and Possible Mechanisms

Gotu kola and Gut Health

1. Ethanol extract of Centella asiatica alleviated dextran sulfate sodium-induced colitis: Restoration on mucosa barrier and gut microbiota homeostasis – Journal of Ethnopharmacology (2021)
 
 
3. Centella asiatica-Derived Endothelial Paracrine Restores Epithelial Barrier Dysfunction in Radiation-Induced Enteritis – Cells (2022) 
 

Gotu Kola and brain Health

1. Recent Updates in Neuroprotective and Neuroregenerative Potential of Centella asiatica- Malaysian Journal of Medical Scineces  (2016) 

2. Effectiveness of Gotu Kola Extract 750 mg and 1000 mg Compared with Folic Acid 3 mg in Improving Vascular Cognitive Impairment after Stroke – Evindence Based Complimentary Alternative Medicine (2016)

2. Positive modulation of cognition and mood in the healthy elderly volunteer following the administration of Centella asiatica – Journal of Ethnopharmacology (2008) 

 

Gotu Kola And Other Conditions

Protective effects of Centella asiatica leaf extract on dimethylnitrosamine-induced liver injury in rats – Molecular Medicine (2016

Lutein Clinical Studies

Maslinic Acid Clinical Studies

1. Maslinic Acid: A New Compound for the Treatment of Multiple Organ Diseases – Molecules (2022)

Concludes that, “MA has a variety of biological activities such as antioxidant, anti-inflammatory, anti-tumor, hypoglycemic and neuroprotective activities, so it has a good preventive and therapeutic effect on various organ-related diseases, such as some cancers, ischemic diseases, diabetes, stroke, and other acute and chronic diseases caused by oxidative stress or inflammation.”  Link: https://www.mdpi.com/1420-3049/27/24/8732

2. Mechanistic Perspectives of Maslinic Acid in Targeting Inflammation – Biochemistry Research International (2015) Link: https://www.hindawi.com/journals/bri/2015/279356/

3. Medicinal Uses of Maslinic Acid: A Review – Journal of Drug Delivery and Therapeutics (2021) Link: https://jddtonline.info/index.php/jddt/article/view/4588/3691

4. The Anticancer Potential of Maslinic Acid and Its Derivatives: A Review – Drug, Design, Development and Therapy (2021) 

5. Maslinic Acid, a Natural Phytoalexin-Type Triterpene from Olives — A Promising Nutraceutical?Molecules (2014)

LEO-HB Technology successfully solves the issues addressed in the conclusion of this study about bioavailability concerns: 

“the amount of maslinic acid in natural edible sources is low, and data about its pharmacokinetics, which we are currently assessing in our laboratory, show that the triterpene has a poor oral bioavailability. From this it would appear that dietary maslinic acid is not sufficient to reach effective concentrations in target organs, thus the compound should be supplied in pure form, i.e. as a nutraceutical.”

Mastic Gum Clinical Studies

Mastic Gum and Gut Health

O.E.A. Clinical Studies

1. Oleoylethanolamide – Science Direct 

O.E.A. and Gut Health

2. Gut microbiota and oleoylethanolamide in the regulation of intestinal homeostasis – Frontiers in Endocrinology (2023)

O.E.A. and Weight Loss, Satiety 

1. Oleic acid-derived oleoylethanolamide: A nutritional science perspective – Progress in Lipid Research (2017) 

2. Oleoylethanolamide: The role of a bioactive lipid amide in modulating eating behaviour – Obesity Reviews (2017) 

3. A systematic review of the effects of oleoylethanolamide, a high-affinity endogenous ligand of PPAR-α, on the management and prevention of obesity –Clinical and Experimental Pharmacology and Physiology  (2020)

4. The lipid messenger OEA links dietary fat intake to satiety–  Cell Metab  (2008) 

O.E.A. and Other Conditions

1. The Effect of Oleoylethanolamide (OEA) Add-On Treatment on Inflammatory, Oxidative Stress, Lipid, and Biochemical Parameters in the Acute Ischemic Stroke Patients: Randomized Double-Blind Placebo-Controlled Study – Oxydative Medicine and Cellular Longevity (2022) OEA in moderate dosage, 300 mg/day, add-on to the standard stroke treatment improves short-term inflammatory, OS, lipid, and biochemical parameters in patients with AIS. This effect might lead to a better long-term neurological prognosis.” 

2. Oleoylethanolamide facilitates PPARα and TFEB signaling and attenuates Aβ pathology in a mouse model of Alzheimer’s diseaseMolecular Neurodegeneration (2023)

 

Oleanolic Acid Clinical Studies

Oleanolic Acid studies on various conditions mentioned: 

  1. Chen, T., et al. (2018). “Effects of oleanolic acid on endothelial function in patients with coronary artery disease: A randomized, placebo-controlled, double-blind trial.” Phytotherapy Research 32(4): 711-717. 
  2. Zhang, L., et al. (2019). “Oleanolic acid ameliorates high-fat diet-induced obesity in rats by modulating the composition and metabolic function of the gut microbiota.” Food & Function 10(8): 4537-4547. 
  3. Yao, Y., et al. (2020). “The effects of oleanolic acid supplementation on blood pressure in humans: A systematic review and meta-analysis of randomized controlled trials.” Phytotherapy Research 34(6): 1242-1254. Oleanolic acid and cognitive function:
  1. Liu, Y., Li, Z. F., Zhang, J. T., Liang, Y. J., & Li, F. (2013). Oleanolic acid improves cognitive impairment induced by chronic cerebral hypoperfusion in rats. Journal of Pharmacological Sciences, 123(4), 294-303. doi: 10.1254/jphs.13015FP Link: 
  2. Jiang, X., Huang, Y., Xu, H., Zhang, X., & Chen, Z. (2014). Oleanolic acid protects against cognitive decline and amyloid β42 accumulation in APP/PS1 mice. Toxicology Letters, 224(3), 330-341. doi: 10.1016/j.toxlet.2013.11.016 Link: 
  3. Kim, D. H., Kim, S., Jeon, S. J., Son, K. H., & Kim, J. (2010). Improvement of cognitive deficit in Alzheimer’s disease patients by long term treatment with Korean Red Ginseng. Journal of Ginseng Research, 34(4), 455-461. doi: 10.5142/jgr.2010.34.4.455 Link: 

Studies on Oleanolic Acid and Heart Health: 

  1. Chen, T., et al. (2018). “Effects of oleanolic acid on endothelial function in patients with coronary artery disease: A randomized, placebo-controlled, double-blind trial.” Phytotherapy Research 32(4): 711-717. 
  2. Zhang, L., et al. (2019). “Oleanolic acid ameliorates high-fat diet-induced obesity in rats by modulating the composition and metabolic function of the gut microbiota.” Food & Function 10(8): 4537-4547. 
  3. Yao, Y., et al. (2020). “The effects of oleanolic acid supplementation on blood pressure in humans: A systematic review and meta-analysis of randomized controlled trials.” Phytotherapy Research 34(6): 1242-1254. 

P.E.A. Clinical Studies

1. Palmitoylethanolamide: A Natural Compound for Health ManagementInternational Journal of Molecular Sciences (2021)  

“It is well tolerated and devoid of side effects in animals and humans. PEA’s actions on multiple molecular targets while modulating multiple inflammatory mediators provide therapeutic benefits in many applications, including immunity, brain health, allergy, pain modulation, joint health, sleep and recovery. PEA’s poor oral bioavailability, a major obstacle in early research, has been overcome by advanced delivery systems now licensed as food supplements.”

2. Palmitoylethanolamide – Advances in clinical chemistry (2023)

P.E.A. and Sleep Management

1. Ultra-micronized Palmitoylethanolamide Effects on Sleep-wake Rhythm and Neuropathic Pain Phenotypes in Patients with Carpal Tunnel Syndrome: An Open-label, Randomized Controlled StudyCNS Neurol Disord Drug Targets (2018)

2. Palmitoylethanolamide for sleep disturbance. A double-blind, randomised, placebo-controlled interventional study Sleep Science and  Practice (2021)

P.E.A. and Pain Management

  1. Palmitoylethanolamide in the Treatment of Chronic Pain: A Systematic Review and Meta-Analysis of Double-Blind Randomized Controlled Trials – Nutrients (2023)
  2. Palmitoylethanolamide in the Treatment of Chronic Pain Caused by Different EtiopathogenesisPain Medicine (2012)

  3. Efficacy of Ultra-Micronized Palmitoylethanolamide in Knee Osteoarthritis: A Randomized, Double-Blind, Placebo-Controlled StudyInflammopharmacology (2019)

  4. Palmitoylethanolamide in the Treatment of Chronic Pain: A Systematic Review and Meta-Analysis of Double-Blind Randomized Controlled Trials – Nutrients (2023)

  5. Effect of ultramicronized-palmitoylethanolamide and co-micronized palmitoylethanolamide/polydatin on chronic pelvic pain and quality of life in endometriosis patients: An open-label pilot study International Journal of Women’s Health (2019)

  6. Palmitoylethanolamide in the Treatment of Chronic Pain: A Systematic Review and Meta-Analysis of Double-Blind Randomized Controlled TrialsNutrients (2023)

  7. Effect of palmitoylethanolamide on inflammatory and neuropathic pain in ratsKorean J Anesthesiol (2017)

  8. Efficacy of Palmitoylethanolamide for Treatment of Pain in Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Randomized, Placebo-Controlled StudyArch Ital Urol Androl (2017)

  9. Palmitoylethanolamide in Fibromyalgia: Results from Prospective and Retrospective Observational Studies – Pain and Therapy (2015)

  10. Palmitoylethanolamide versus a nonsteroidal anti-inflammatory drug in the treatment of temporomandibular joint inflammatory painJournal of Orofacial Pain (2012)

  11. Efficacy of Palmitoylethanolamide (Levagen+TM) Compared to Ibuprofen for Reducing Headache Pain Severity and Duration in Healthy Adults: A Double-Blind, Parallel, Randomized Clinical TrialFood and Nutrition Sciences (2022)

  12. ALIAmides Update: Palmitoylethanolamide and Its Formulations on Management of Peripheral Neuropathic PainInternational Journal of Molecular Sciences (2020) 

  13. Palmitoylethanolamide in the Treatment of Chronic Pain: A Systematic Review and Meta-Analysis of Double-Blind Randomized Controlled Trials – Nutrients (2023)

  14. Novel Approach to the Treatment of Neuropathic Pain Using a Combination with Palmitoylethanolamide and Equisetum arvense L. in an In Vitro Study – International Journal od Molecular Sciences (2023)

  15. Tolerability of Palmitoylethanolamide in a Pediatric Population Suffering from Migraine: A Pilot Study – Pain Research and Management  (2020)

Piperine Clinical Studies

Urolithin Clinical Studies

Urolithin Studies and Various Conditions Mentioned: 

  1. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodentsNature Medicine (2016)

  2. Urolithin A exerts antiobesity effects through enhancing adipose tissue thermogenesis in mice – Plos Biology (2020) 

  3. Urolithin A ameliorates oxidative stress and mitochondrial dysfunction induced by ischemia/reperfusion injury in cardiomyocytes Plos Biology (2020)

  4. The gut microbiota metabolite urolithin A inhibits NF-κB activation in LPS stimulated BMDMs – Scientific Reports (2021)

  5. Ameliorative Effects of Gut Microbial Metabolite Urolithin A on Pancreatic Diseases – Nutrients (2022)

  6. Urolithin A attenuates memory impairment and neuroinflammation in APP/PS1 mice – Neuroinflammation (2019)

  7. Urolithin A, a pomegranate metabolite, protects pancreatic β cells from apoptosis by activating autophagy – Journal of Ethnopharmacology (2021)

  8. “The Urolithin Metabolites, Urolithin A and Urolithin B, Inhibit Androgen Independent Prostate Cancer Cell Growth and Induce Apoptosis via Cell Cycle Arrest.” 

  9. “Urolithin A attenuates ox-LDL-induced endothelial dysfunction partly by modulating microRNA-27 and ERK/PPAR-γ pathway.” 

Urolithin and Gut Health: 

  1. “Urolithin A, a metabolite derived from ellagic acid, enhances intestinal barrier function in vitro and in vivo.” – This study found that urolithin A helped to improve intestinal barrier function in vitro and in vivo, suggesting that it may have a positive impact on gut health.

  2. “Urolithin A attenuates the proinflammatory response in intestinal epithelial cells and macrophages.” –  This study demonstrated that urolithin A can reduce the production of pro-inflammatory cytokines in intestinal epithelial cells and macrophages, suggesting that it may have anti-inflammatory effects in the gut.

  3. “Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents.” – This study investigated the effects of urolithin A on lifespan and muscle function in rodents, but also found that it increased the abundance of Akkermansia muciniphila in the gut.

  4. “Urolithin metabolites improve skeletal muscle mitochondrial function in healthy and myotubes from men with obesity.” – This study investigated the effects of urolithin metabolites on skeletal muscle mitochondrial function, but also found that they increased the abundance of beneficial gut bacteria, including Akkermansia muciniphila.

Ursolic Acid Clinical Studies

Ursolic acid and Brain Health:

1. Dabaghzadeh, F., Ghaeli, P., Mohammadi, H., & Hajizadeh Moghaddam, A. (2018). Effect of ursolic acid on cognitive impairment induced by intracerebroventricular streptozotocin injection in rats. Clinical Psychopharmacology and Neuroscience, 16(4), 423-432. doi: 10.9758/cpn.2018.16.4.423 

This study investigated the effects of ursolic acid on cognitive function in rats injected with a substance that can induce cognitive impairment. The results showed that ursolic acid improved memory and learning abilities, as well as reducing oxidative stress and inflammation in the brain.

2. Hsiao, Y. H., Chen, Y. H., Huang, S. S., Ho, S. Y., Wang, C. H., Chiou, T. W., & Chen, C. J. (2018). Neuroprotective effects of ursolic acid on cognitive and spatial memory impairments induced by intermittent hypoxia. Behavioural Brain Research, 343, 115-123. doi: 10.1016/j.bbr.2018.02.019 

This study investigated the effects of ursolic acid on cognitive function in rats exposed to intermittent hypoxia, a condition that can cause cognitive and spatial memory impairments. The results showed that ursolic acid improved cognitive function and reduced brain inflammation and oxidative stress.

3. Liu, H., Li, W., & Li, J. (2017). Effects of ursolic acid on cognitive deficits and oxidative stress in a streptozotocin-induced rat model of Alzheimer’s disease. Journal of Drug Targeting, 25(5), 454-461. doi: 10.1080/1061186X.2017.1281377 

This study investigated the effects of ursolic acid on cognitive deficits and oxidative stress in rats with induced Alzheimer’s disease. The results showed that ursolic acid improved cognitive function, reduced oxidative stress, and increased the expression of proteins involved in brain plasticity and function