Amazon Blend Clinical Information

AJO SACHA () is a wild jungle garlic said to have originated in the Amazon rainforest, ​ ​ but it has since spread to several other parts of the world with similar climates. It has been used by indigenous communities for centuries as a “spiritual” capable of driving away evil spirits, clearing 1,13 negative energy from the mind and body, and used for good luck. ​ Ajo Sacha contains several of the ​ 3,4 main sulfur compounds that garlic does, such as allicin and ursolic acid. ​ These compounds have ​ been well documented within evidence based literature demonstrating antimicrobial, anti-inflammatory, and antioxidant properties, as well as cellular protective actions in the lungs, kidneys, liver, and brain.

Clinical Efficacy and Research Related to Ajo Sacha

Antimicrobial effects. Antimicrobial actions against plant viruses, fungi, and bacteria have been ​ reported which may explain why traditionally Ajo Sacha has been used to treat colds, flu, pneumonia 5,6,10 and other upper respiratory infections. ​ An in-vitro assay study in 2005 showed that the antifungal ​ action of the Ajo Sacha leaf extract was as potent as a commonly used antifungal drug, clotrimazole, at 11 very low doses. ​ The presence of coumarins in the Ajo Sacha plant, along with its phenolic content, is ​ 12 associated with the medicinal actions attributed to this plant. ​ Studies have cited several popular ​ medicinal uses for the treatment of cough, nausea, fever, diarrhea, among others.4,12,13,14 ​

Anti-inflammatory effects. A study performed in 2009 showed that the essential oil of this species is ​ composed of various sulfur compounds, which showed anti-inflammatory activity and may be 4 responsible for the medicinal actions of the plant. ​ Ajo Sacha has also been shown to inhibit COX, ​ which is an enzyme required in the inflammatory process. Inhibition of COX can provide relief from the symptoms of inflammation and pain as demonstrated through Ajo Sacha’s use for the treatment of 7 arthritis and rheumatism. M​ ore recent reports show that Ajo Sacha’s anti-inflammatory actions can also ​ be explained by the plant’s ability to regulate the immune system and decrease the production of immune cells that cause inflammation.1,8 ​

Antioxidant effects. Several studies have reported very strong antioxidant actions and attributed them ​ 3,9,14 to isolated and tested organosulfur compounds, ursolic acid, and anthocyanin. ​ The sulfur ​ ​ compounds in Ajo Sacha have been reported to lower cholesterol and have antioxidant effects in both humans and animals.2,8,10 ​

Cellular Protective effects. Ajo sacha is a rich source of a well-known natural terpene, called ursolic ​ acid, which has been documented with cellular protective actions in the lungs, kidneys, liver and brain.3 ​ Under physiological concentrations in mice, ursolic acid has been shown to induce programmed cell death in defective red blood cells, reduce muscle atrophy while stimulating muscular growth, shown potential for cardioprotection, and induce neural regeneration after sciatic nerve injury.10,15 16, 17 ​

SANGRE DE GRADO (croton lechleri) is a medium-sized tree found in many regions of South ​ America. It is often called "Dragon's Blood" due to a red latex or sap that is extracted upon felling the ​ tree and scoring the bark. This latex is the primary part of Sangre de Grado used for medicinal purposes due to the protective antioxidant phenols and anti-inflammatory compounds found within.22,23 ​ ​ Reviews of these chemical constituents of the sap have been widely published and scientists have attributed many of the biologically active properties of the sap to two main “active” constituents: an 18-21 alkaloid named taspine and a lignan named dimethylcedrusine. A​ purified constituent of sangre de ​ ​ ​ ​ grado known as crofelemer (Mytesi, formerly Fulyzaq and SP-303) is an FDA-approved drug for the 18,22 treatment of non-infectious diarrhea in HIV and AIDS patients receiving antiretroviral drugs. F​ or ​ centuries, the sap has been painted on wounds to stop bleeding, accelerate healing, and to seal and protect injuries from infection. It is used externally by indigenous tribes and local people in Peru for wounds, fractures, and hemorrhoids, internally for gastrointestinal problems such as hemorrhoids.19-21 ​ Clinical Efficacy and Research Related to Sangre de Grado Antibacterial and Antiviral effects. Several phenolic compounds and diterpenes, as well as the ​ 24-26 essential oil from the plant, have demonstrated antibacterial activity in animal studies. ​ A​ ntiviral ​ effects have also been seen with Sangre de Grado extracts and may be related to viral penetration of ​ ​ the cell membrane. Crofelemer demonstrates broad in vitro activity against DNA and RNA viruses, including respiratory syncytial virus, influenza A, parainfluenza virus, herpesvirus types 1 and 2, and 27-29 hepatitis A and B. ​ T​ he mechanism of sangre de grado's antibacterial effects is unclear. ​ Analgesic effects. In vitro and animal research suggests that Sangre de Grado sap blocks the ​ activation of sensory afferent nerves at the prejunctional and postjunctional levels, leading to relief of pain, burning, and itching caused by neurogenic inflammation.19,30,31 ​

Anti-inflammatory effects. The alkaloid constituent taspine, isolated from Sangre de Grado, has ​ demonstrated anti-inflammatory effects in animal models of pain and inflammation, with anti-inflammatory activity similar to or greater than indomethacin, an FDA approved nonsteroidal anti-inflammatory drug (NSAID).19,32 ​

Gastrointestinal effects. Animal research suggests that Sangre de Grado promotes the healing of ​ gastric ulcers. This may be explained by reduced gene expression of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), inducible nitric oxide synthase (iNOS), interleukin (IL)-1beta, IL-6, and cyclooxygenase-2 (COX-2), which has been demonstrated in the gastric 19,31 epithelium of rats with acetic-acid induced ulcers treated with sangre de grado sap. C​ rofelemer, a ​ purified constituent of Sangre de Grado, has been approved by the FDA for symptomatic relief of 37,38 noninfectious diarrhea in patients with HIV/AIDS who are receiving antiretroviral therapy. C​ linical ​ studies have been conducted in acute infectious diarrhea, diarrhea in patients with HIV, and diarrhea-predominant irritable bowel syndrome (IBS).27,36,37 ​

Immunomodulating effects. In vitro research shows that Sangre de Grado acts as an ​ immunomodulator (a substance that stimulates or suppresses the immune system to help the body fight infection or other disease) by inhibiting both classical and alternative complementary pathways which inhibit the proliferation of activated T cells.33 ​

Wound-healing effects. The wound-healing effects of Sangre de Grado may be due to a variety of ​ factors. These include the antimicrobial, anti-inflammatory, and protein-binding properties of polyphenol constituents; the antioxidant properties of procyanidin constituents; and the ability of the sap to cover 19 the wound, preventing infection from surface microbes. ​ With respect to specific constituents, the ​ alkaloid taspine and the lignan dimethylcedrusine appear to play a role in wound healing.34,19,35 ​

CANNABIDIOL (CBD)

Cannabis is one of the first to have been used as a medicine and for religious ceremonies, the 43 first accounts of its use for these purposes stretching back 5000 years. ​ Cannabis contains over 400 ​ 39 different chemicals, known as cannabinoids, making it a complex plant. ​ The chemical that leads to the ​ psychoactive “high” associated with cannabis, delta-9-tetrahydrocannabinol (THC), is only one of over 40 400 found in the plant. ​ While THC can be controversial due to its psychoactive properties, research is ​ beginning to show therapeutic potential with cannabidiol (CBD). Cannabidiol makes up around 40% of 40 cannabis extracts, and unlike THC, does not cause a psychoactive high. ​ According to the World ​ ​ Health Organization, CBD exhibits no effects indicative of any abuse or dependence potential in 41 humans. ​ As of June 2018, the only legal form of CBD that is FDA approved is Epidiolex, a ​ 42 prescription medication used to treat certain seizure disorders. ​ There is also evidence that CBD may ​ ​ be a useful treatment for a number of other medical conditions. However, this research is considerably less advanced than for treatment of epilepsy. For most indications, there is only pre-clinical evidence, while for some there is a combination of pre-clinical and limited clinical evidence. The range of conditions for which CBD has been assessed is diverse, consistent with its antioxidant, ​ anti-inflammatory, anticonvulsant, and neuroprotective qualities.54-56 ​

Clinical Efficacy and Research Related to Cannibidiol

Antiepileptic effects: The clinical use of CBD is most advanced in the treatment of epilepsy. In clinical ​ trials, CBD has been demonstrated as an effective treatment for at least some forms of epilepsy, with one pure CBD product (Epidiolex®). The use of CBD for this purpose is based on a number of studies 41,46 in animals dating back to the 1970s. ​ These studies demonstrated the anti-seizure activity of ​ 47,48 cannabidiol in a number of animal models. ​ Based on this research, cannabidiol has been tested in ​ patients with epilepsy and a variety of syndromes, including Dravet, Lennox-Gastaut, Sturge-Weber, and tuberous sclerosis complex.49-53 ​

Anti-inflammatory effects: CBD has been shown to influence inflammatory signal molecules ​ (cytokines) that are secreted from immune cells to promote inflammation. It has been shown to modulate tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and interferon (IFN)-gamma and 57-59 suppress chemokine production. ​ In a mouse model of rheumatoid arthritis, CBD improved arthritis ​ symptoms and blocked disease progression.60 ​ Immunomodulating effects: In vivo and in vitro research suggest that CBD modulates immune ​ system function, including the suppression of cell-mediated and humoral immunity and the inhibition of antigen presentation, humoral response, and proliferation, maturation, and migration of immune cells.61 ​

Neuroprotective effects: In vivo and in vitro research suggests that CBD may have neuroprotective ​ effects in neurodegenerative diseases, such as Alzheimer’s disease and Huntingto’s disease. While the mechanism of these effects is still unclear, it is thought to relate to CBDs anti-inflammatory and antioxidant effects.63-67 ​

SPIRIT SONGS BOTANICALS - AMAZON BLEND - FREQUENTLY ASKED QUESTIONS

What is the correct dosage? Shake vigorously before use. Start with ¼ dropper (0.25ml) twice daily with food, preferably morning and bedtime. Gradually increase to ½ dropper (0.5 ml) twice per day. Make sure to start low and go slow. Use the same dose for several days. Observe the effects and if necessary adjust the amount.

Are there any interactions with drugs?

There have been no reported drug interactions with Ajo Sacha or Sangre De Grado. However, there are documented drug-herb conditions reported with Cannabidiol at high doses. At low doses of CBD, less than 150mg total per day, it is unlikely that significant drug-herb interactions will occur. One dropperful of ​ the Amazon Blend contains 1ml or 13.3mg of CBD. However, it is always possible that drug-herb ​ interactions can occur so it is always safest to talk with a healthcare professional if there are any questions.

In general, CBD and other plant cannabinoids can potentially interact with many pharmaceuticals by inhibiting the activity of cytochrome P450, a family of liver enzymes. If you are taking a medication where maintaining a certain blood level is critical- such as anti-seizure, anti-viral, blood-thinning medications- talk with your healthcare provider or pharmacist before trying the Amazon Blend.

See below for a complete list of medications that have the potential to interact.

Are there any interactions with herbs and supplements? Cannabidiol can cause sleepiness or drowsiness. Using it along with other herbs and supplements that have the same effect might cause too much sleepiness. Some of these herbs and supplements include calamus, California poppy, catnip, hops, Jamaican dogwood, kava, L-tryptophan, melatonin, sage, SAMe, St. John's wort, sassafras, skullcap, and others.

Are there safety concerns? There is not enough reliable information about the safety of taking Amazon Blend ingredients if you are pregnant or breast-feeding. Stay on the safe side and avoid use.

Are there potential side effects? Some reported side effects of cannabidiol include dry mouth, low blood pressure, light-headedness, and drowsiness. Signs of liver injury have also been reported in some patients, but this is rare.

Potential Drug Interactions45 ​

Major interaction - Do not take combination Clobazam (Onfi) valproic acid (Valproate)

Moderate interaction - Be cautious with this combination - Talk to your health provider eslicarbazepine (Aptiom) disulfiram (Antabuse) chlorzoxazone (Lorzone) ketamine (Ketalar) theophylline (Theo-Dur, others) phenobarbital amitriptyline (Elavil) orphenadrine (Norflex) haloperidol (Haldol) secobarbital (Seconal) ondansetron (Zofran) dexamethasone (Decadron) propranolol (Inderal) pantoprazole (Protonix) verapamil (Calan, Isoptin, others) diazepam (Valium) omeprazole (Prilosec, Omesec) carisoprodol (Soma) clozapine (Clozaril, FazaClo) nelfinavir (Viracept) progesterone (Prometrium, others) diclofenac (Cataflam, Voltaren) lansoprazole (Prevacid) meloxicam (Mobic) flutamide (Eulexin) piroxicam (Feldene) oxaliplatin (Eloxatin) celecoxib (Celebrex) erlotinib (Tarceva) amitriptyline (Elavil) chlormethiazole (Heminevrin) warfarin (Coumadin) coumarin glipizide (Glucotrol) methoxyflurane (Penthrox) losartan (Cozaar) halothane (Fluothane) progesterone (Endometrin, Prometrium) testosterone nifedipine (Adalat CC, Procardia XL) cyclosporine (Sandimmune)

This product has not been reviewed by the FDA to determine whether it is safe or effective and is not subject to the quality standards and safety information collection standards that are applicable to most prescription drugs. This information should not be used to decide whether or not to take this product. This information does not endorse this product as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this product. It does not include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this product. This information is not specific medical advice and does not replace information you receive from your healthcare provider. You should talk with your health care provider for complete information about the risks and benefits of using this product.

References

AJO SACHA

1 Taylor, Leslie. Wealth of the Rainforest, Pharmacy to the World. Tropical Plant database online ​ http://www.rain-tree.com/mansoa.htm. ​ 2 Yeh, Y., et al. "Cholesterol-lowering effect of garlic extracts and organosulfur compounds: human and animal ​ studies." J. Nutr. 2001 Mar; 131(3s): 989S-993S. ​

3 Woniak, L., et al "Ursolic Acid--A pentacyclic triterpenoid with a wide spectrum of pharmacological activities." ​ ​ Molecules 2015; 20(11): 20614-20641.

4 Zoghbi, M., et al. "The Mansoa (): A source of organosulfur compounds. Braz. J. Pharmacog. ​ ​ 2009; 19: 795-804. ​

5 Rana, B. K., et al. "Antifungal activity of an aqueous extract of leaves of garlic creeper (Adenocaymma alliaceum ​ Miers.)." Pharma. Biol. 1999; 37(1):. 13-16. ​

6 Freixa, B., et al. Screening for antifungal activity of nineteen Latin American plants." Phytother. Res. 1998; 12: ​ ​ 27-43.

7 Dunstan, C., et al. "Evaluation of some Samoan and Peruvian medicinal plants by prostaglandin biosynthesis and ​ rat ear oedema assays." J. Ethnopharmacol. 1997; 57: 35-56. ​

8 Hamann, R., et al. "Mansoa alliacea extract presents antinociceptive effect in a chronic inflammatory pain model in ​ mice through opioid mechanisms." Neurochem Int. 2018 Nov 27; 122: 157-169. ​

9 Prasad, K.,et al. "Antioxidant activity of allicin, an active principle in garlic." Mol. Cellular. Biochem. 1995; 148: ​ ​ ​ 183-189.

10 Salazar, et al. Ethnopharmacology, biological activity and chemical characterization of Mansoa alliacea. 2017; A ​ ​ review about a promising plant from Amazonian region. 10.3390/mol2net-03-04617.

11 Chirunthorn, R., et al. "Study on biological activities of Mansao hymenaea (DC.) A. Gentry leaf extracts." ​ ​ Songklanakarin J. Sci. Technol. 2005; 27(Suppl. 2): 489-495.

12 Gonsior E ,et al. Protective antiallergic effects of a new coumarin compound (BM 15.100) in experimental asthma. ​ ​ International Journal of Clin Pharma and Biopharmacy, 1979; 17(7): 283-289.

13 Tudela-Talavera P, et al. Cultural importance and use of medicinal plants in the shipibo-conibo native community ​ of Vencedor (Loreto) Peru. Ethno Res Applicat, 2016; 14: 533-548 ​

14 Desmachelier C,et al. Total reactive antioxidant potential (TRAP) and total antioxidant reactivity (TAR) of ​ medicinal plants used in Southwest Amazonia (Bolivia and Peru). Int J Pharmacog, 2007; 35: 1-9. ​

15 Jilani K ,et al. "Triggering of erythrocyte cell membrane scrambling by ursolic acid". J Nat Prod. 74 (10): ​ ​ 2181–2186.

16 Kunkel, S. et al. "MRNA Expression Signatures of Human Skeletal Muscle Atrophy Identify a Natural Compound ​ that Increases Muscle Mass". Cell Metabolism; 2011. 13 (6): 627–638. ​

17 Liobikas J,et al. "Uncoupling and antioxidant effects of ursolic acid in isolated rat heart mitochondria";2011. J. Nat. ​ ​ Prod. 74 (7): 1640–4.

SANGRE DE GRADO

18 Natural Medicines Database. “Sangre de Grado.” Professional Drug Monograph. Accessed online July 2019. ​ ​

19 Jones K. Review of sangre de drago (Croton lechleri)--a South American tree sap in the treatment of diarrhea, ​ inflammation, insect bites, viral infections, and wounds: traditional uses to clinical research. J Altern Complement ​ Med. 2003;9(6):877-896.

20 Gupta D, Bleakley B, Gupta RK. Dragon's blood: Botany, chemistry and therapeutic uses. J Ethnopharmacol. ​ ​ 2008;115(3):361-380.

21 Taylor, Leslie. Wealth of the Rainforest, Pharmacy to the World. Tropical Plant database online http://www.rain-tree.com/sangre.htm. ​

22 Fulyzaq [package insert]. Salix Pharmaceuticals, Inc.; Raleigh, NC: December 2012. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202292s000lbl.pdf. ​

23 Facts and Comparisons Database. “Sangre de Grado.” Professional Drug Monograph. Accessed online July 2019. ​ ​ ​

24 Cai Y, Chen ZP, Phillipson JD. Clerodane diterpenoids from Croton lechleri. Phytochemistry. 1993;34(1):265-268. ​ ​

25 Rossi D, et al. Evaluation of the mutagenic, antimutagenic and antiproliferative potential of Croton lechleri (Muell. ​ Arg.) latex. Phytomedicine. 2003;10(2-3):139-144. ​ 26 Chen ZP, et al. Studies on the anti-tumour, anti-bacterial, and wound-healing properties of dragon's blood. Planta ​ ​ Med. 1994;60(6):541-545. 27 Cottreau J, et al. Crofelemer for the treatment of secretory diarrhea. Expert Rev Gastroenterol Hepatol. ​ ​ 2012;6(1):17-23. 28 Crutchley RD, et al. Crofelemer, a novel agent for treatment of secretory diarrhea. Ann Pharmacother. ​ ​ 2010;44(5):878-884. 29 Ubillas R, et al. SP-303, an antiviral oligomeric proanthocyanidin from the latex of Croton lechleri (Sangre de ​ Drago). Phytomedicine. 1994;1(2):77-106. ​ 30 Pereira, U., et al. Effects of sangre de drago in an in vitro model of cutaneous neurogenic inflammation. ​ ​ Exp.Dermatol. 2010;19(9):796-799. 31 Miller, M. J., et al. Inhibition of neurogenic inflammation by the Amazonian herbal medicine sangre de grado. ​ J.Invest Dermatol. 2001;117(3):725-730. ​

32 Perdue GP, et al. South American plants II: taspine isolation and anti-inflammatory activity. J Pharm Sci ​ ​ 1979;68:124-6.

33 Risco, E., et al. Immunomodulatory activity and chemical characterisation of sangre de drago (dragon's blood) ​ from Croton lechleri. Planta Med. 2003;69(9):785-794. ​

34 Vaisberg AJ, et al. Taspine is the cicatrizant principle in Sangre de Grado extracted from Croton lechleri. Planta ​ ​ Med 1989;55:140-3.

35 Porras-Reyes, B. H., et al. Enhancement of wound healing by the alkaloid taspine defining mechanism of action. ​ ​ Proc.Soc.Exp.Biol.Med. 1993;203(1):18-25. 36 Clay PG, et al. Noninfectious diarrhea in HIV seropositive individuals: a review of prevalence rates, etiology, and ​ management in the era of combination antiretroviral therapy. Infect Dis Ther. 2014;3(2):103-122. ​ 37 Frampton JE. Crofelemer: a review of its use in the management of non-infectious diarrhoea in adult patients with ​ HIV/AIDS on antiretroviral therapy. Drugs. 2013;73(10):1121-1129. ​ 38 Hornby PJ. Drug discovery approaches to irritable bowel syndrome. Expert Opin Drug Discov. 2015;10(8):809-824 ​ ​

CANNABIDIOL

39 Atakan Z. Cannabis, a complex plant: different compounds and different effects on individuals. Therapeutic ​ ​ Advances in Psychopharmacology. 2012;2(6):241-254. 40 Pamplona FA, da Silva LR, Coan AC. Potential Clinical Benefits of CBD-Rich Cannabis Extracts Over Purified ​ CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis. Frontiers in Neurology. 2018;9:759. ​ 41 WHO Expert Committee on Drug Dependence :Forty-Eighth meeting. Geneva: World Health Organization; June ​ ​ 2018. WHO technical report series. ​ 42 Epidiolex. GW Pharmaceuticals. https://www.gwpharm.com/healthcare-professionals/epidiolex. Accessed July 3, ​ ​ 2019

43 Mechoulam R.The pharmacohistory of Cannabis sativa Cannabinoids as Therapeutic Agents ed. Mechoulam, R. ​ ​ ​ ​ pp. 1–19.Boca Raton, FL: CRC Press

44 National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and ​ Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National ​ Academies Press.

45 Natural Medicines Database. “Cannabidiol.” Professional Drug Monograph. Accessed online July 2019. ​ ​ 46 Do Val-da Silva, R.A., et al., Protective effects of cannabidiol against seizures and neuronal death in a rat model ​ of mesial temporal lobe epilepsy. Frontiers in Pharmacology, 2017. ​ 47 Ames, F. R. and Cridland, S. Anticonvulsant effect of cannabidiol. S.Afr.Med.J. 1-4-1986;69(1):14. ​ ​ 48 Cunha, J. M., et al. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. ​ ​ Pharmacology 1980;21(3):175-185.

49 Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet Syndrome. N ​ ​ Engl J Med. 2017 May 25;376(21):2011-2020.

50 Hess EJ, Moody KA, Geffrey AL, et al. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous ​ sclerosis complex. Epilepsia. 2016 Oct;57(10):1617-24. ​ 51 Devinsky O, Marsh E, Friedman D, et la. Cannabidiol in patients with treatment-resistant epilepsy: an open-label ​ interventional trial. Lancet Neurol. 2016 Mar;15(3):270-8. ​ 52 Kaplan EH, Offermann EA, Sievers JW, Comi AM. Cannabidiol treatment for refractory seizures in Sturge-Weber ​ Syndrome. Pediatr Neurol. 2017 Jun;71:18-23.e2. ​ 53 Devinsky O, Patel AD, Cross JH, et al. Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome. ​ ​ N Engl J Med. 2018 May 17;378(20):1888-1897.

54 Fasinu, P.S., et al., Current Status and Prospects for Cannabidiol Preparations as New Therapeutic Agents. ​ ​ Pharmacotherapy, 2016. 36(7): p. 781-96.

55 Iffland, K. and F. Grotenhermen, An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data ​ and Relevant Animal Studies. Cannabis and Cannabinoid Research, 2017. 2(1): p. 139-154. ​ 56 Devinsky, O., et al., Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other ​ neuropsychiatric disorders. Epilepsia, 2014. 55(6): p. 791-802. ​ 57 Watzl, B., et al. Marijuana components stimulate human peripheral blood mononuclear cell secretion of ​ interferon-gamma and suppress interleukin-1 alpha in vitro. Int J Immunopharmacol. 1991;13(8):1091-1097. ​ 58 Srivastava, M. D., et al. Delta9 tetrahydrocannabinol and cannabidiol alter cytokine production by human immune ​ cells. Immunopharmacology 1998;40(3):179-185. ​ 59 Formukong EA, Evans AT, Evans FJ. Analgesic and anti-inflammatory activity of constituents of Cannabis sativa ​ L. Inflammation 1988;12(4):361-71. ​ 60 Malfait AM, et al. The non-psychoactive cannabis-constituent cannabidiol is an oral anti-arthritic therapeutic in ​ murine collagen-induced arthritis. Proc Natl Acad Sci USA 2000;97:9561-6. ​ 61 Booz GW. Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative ​ stress. Free Radic Biol Med 2011;51(5):1054-61. ​ 62 Iuvone, T., et al. Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on ​ beta-amyloid-induced toxicity in PC12 cells. J Neurochem. 2004;89(1):134-141. ​ 63 Izzo AA, et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends ​ ​ Pharmacol Sci 2009;30(10):515-27.

64 Zuardi AW. Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Rev Bras Psiquiatr ​ ​ 2008;30(3):271-80.

65 Bisogno T, et al. The role of the endocannabinoid system in Alzheimer's disease: facts and hypotheses. Curr ​ ​ Pharm Des 2008;14(23):2299-3305.

66 Iuvone T, et al. Cannabidiol: a promising new drug for neurodegenerative disorders? CNS Neurosci Ther ​ ​ 2009;15(1):65-75.

67 Esposito G, et al.. Cannabidiol in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta ​ and iNOS expression. Br J Pharmacol 2007;151(8):1272-9. ​