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Beyond CB 1 and CB2

So far, there are about 22 receptors that marijuana interacts with. We cannot say this is our endocannabinoid system, since our own endocannabinoids do not interact with all of these receptors. Maybe, we can call it the exocannabinoid system!

 

Pharmaceutical companies develop drugs to interact selectively with one or two receptors in this system, but also come with a bunch of horrible side effects. Cannabis oil with a mix of CBD, CBG, Delta-9 THC, and a few select terpenes will interact with all of the receptors. Maximize your health with marijuana!

TRPA 1 The TRPA1 receptor acts as an irritant sensor for our body, and can be useful for treating pain Cannabinoids that activate TRPA1 helps to desensitize our response to mustard oil and capsaicin, as well as having antinociceptive, antiallodynic and anti-inflammation effects. Cannabinoids: CBD, CBDA, CBG, CBC, and Delta 9-THC. Terpenes: Eugenol, Eucalyptol [1,8-cineole (inhibits) and 1,4-cineole (activates)] Pharmaceutical drug: Algomedix - non-opioid, non-addictive, TRPA1 antagonist for the treatment of acute and chronic pain. Other ligands (some healing and some harmful): Mustard oil, acrolein, vehicle exhaust, and metabolic byproducts of chemotherapeutic agents, cinnamaldehyde, gingerol, methyl salicylate, allicin (some need extremely high doses to activate TRPA1). An effective analgesic compound would activate TRPM8 and inhibit TRPA1. Mustard oil applied to the skin produces pain, reddening, swelling, edema, and plasma extravasation, and painful hypersensitivity. Mustard oil induces pain by releasing calcitonin gene-related peptide and Substance P from sensory nerve endings. TRPV 1 The typical function of the TRPV1 receptor is act as a heat sensor. Capsaicin, heat (>43oC), and many other ligands (see below for a list) can interact with this receptor. An over-expression of TRPV1 can be found in: Rheumatoid arthritis Inflammatory bowel disease Vulvar allodynia Prurigo nodularis Inflammatory hyperalgesia Gastroesophageal reflux disease Irritable bowel syndrome Some cancers involving prostate, bladder, pancreas, tongue, skin, liver, and colon. One cause of the over-expression of TRPV1 is a toxin (toxin A) that is released by the bacteria Clostridium difficile (aka c-diff). Artificial sweeteners not only activate TRPV1, but also makes the receptor more sensitive to acid and heat. Cholesterol has been found to increase neurogenic pain. Cholesterol dilates the TRPV1 pore allowing increased flow of calcium ions into the cell. When TRPV1 is activated with a beneficial ligand, such as capsaicin, Some cancer cells can die through apoptosis or necrosis. This is caused by the calcium flow into the cell with TRPV1 activation. Cannabinoids that interact with TRPV1: CBD, CBDA, CBG. Terpenes that interact with TRPV1: Eugenol Eucalyptol is a possible antagonist, but it is still under research Geranylacetone (agonist) Myristicin (antagonist) β-pinene, sabinene, and γ-terpinene (all three to a lesser extent) Pharmaceuticals: SB-705498 is a TRPV1 antagonist made by GlaxoSmithKline for treating intranasal rhinitis PAC-14028 is a TRPV1 antagonist made by Amore Pacific for treating oral atopic dermatitis SYL-1001 is a TRPV1 expression inhibitor made by Sylentis for treating ophthalmic dry eye pain Capsaicin (Qutenza) is a TRPV1 agonist made by NeurogesX which is a topical patch or topical cream for treating neuropathic pain Zucapsaicin (Zuacta) is a TRPV1 agonist made by Winston Laboratories which is a topical cream for treating osteoarthritis Other ligands (some healing and some harmful): capsaicin, heat (>43oC), cholesterol, C-diff Toxin A, endogenous cannabinoids: anandamide, N-arachidonoyl-dopamine, some endovanilloids, artificial sweeteners, inorganic cations, polyamines, spider toxins. Piperine from black pepper, eugenol from cloves and zingerone, gingerols, present in raw ginger, and shogaols, which are dehydration products of gingerols present in steamed ginger, alicin (garlic and onion), camphor, nitric oxide, CuSO4 (copper II sulfate), ZnSO4 (Zinc Sulfate), and FeSO4 (Iron II Sulfate). The last 3 salts that can produce a metallic taste. Non-toxic and non-psychoactive CBD has been found to be an effective antihyperalgesic for treating neuropathy and rheumatoid arthritis. Since the expression of TRPV1 is over-expressed in conditions like rheumatoid arthritis, higher doses of CBD may be needed. Topicals can only interact with a certain amount of receptors, CBD edibles and tinctures may be needed for conditions with an over-expression of TRPV1. Capsaicin topicals and creams are widely available to help with neurogenic pain, arthritis, muscle pain, joint pain, etc. Capsaicin does burn and cause redness of the skin. Some people can handle the heat, while many others cannot. on Sep 13, 2012, the FDA alert came out for capsaicin: Over-The-Counter Topical Muscle and Joint Pain Relievers: Drug Safety Communication - Rare Cases of Serious Burns. This is more of a fun fact: A component from some spider and scorpion venoms (vanillotoxins) also activate TRPV1. Not all the venoms act the same. A tarantula (Psalmopoeus cambridgei) from the West Indies activates TRPV1. While the North American funnel web spider (Agelenopsis aperta), is a potent inhibitor of TRPV1. TRPV 2 TRPV2 receptors are located in many parts of the body including brain, skin, spleen, lung, stomach, intestines, bladder, prostate, peripheral blood, immune system, and can be over-expressed in some cancers as well. The white blood cells that eats bacteria, macrophages, has a TRPV2 receptor. That receptor needs to be active for phagocytosis to occur. Several things can activate this including CBD, CBN (1), and Delta 9-THC. TRPV2 deficiency has shown impaired phagocytosis. A rat study has shown with TRPV2 deficiency, there was a 60x greater bacterial load (tested against Listeria). The activation of the TRPV2 receptors in the pancreatic β-cells will stimulate insulin secretion. The following will interact with TRPV2 receptors: Cannabinoids: CBD, CBN, and Delta 9-THC. Pharmaceutical drug: Probenecid Probenecid has been developed to treat the following: Diabetes|Diabetes Mellitus Type 2 by Novo Nordisk A/S (NCT03466567) and Theracos (NCT03296800) Uncomplicated Urinary Tract Infections by Iterum Therapeutics US Limited (NCT03354598) Intra Abdominal Infections by Iterum Therapeutics US Limited (NCT03358576) Complicated Urinary Tract Infections by Iterum Therapeutics US Limited (NCT03357614) TRPM 8 Cannabinoids: CBD, CBDA, CBG, and Delta 9-THCA. Terpenes: Eucalyptol (1,8 cineole and 1,4-cineole), geraniol, linalool, hydroxycitronellal Pharmaceutical drug: D-3263 hydrochloride Other Ligands: Cholesterol, Ilicin, menthol (also found in peppermint oil) TRPM8 has many functions, including: acting as a thermal sensor in the peripheral nervous system somatosensory in the prostate part of making macrophages function properly over-expressed in several cancers (prostate, pancreatic, breast, lung, colorectal, melanoma, bladder, neuroblastoma, glioblastoma, neuroendocrine, oral squamous, and osteosarcoma) TRPM 8 is under going research as a treatment for prostate cancer, migraines, and chronic pain. Big Pharma has an enteric-coated TRPM 8 agonist called D-3263 hydrochloride. The below paragraph was taken from their website: https://www.cancer.gov/publications/dictionaries/cancer-drug/def/enteric-coated-trpm8-agonist-d-3263-hydrochloride "This agent may decrease dihydrotestosterone (DHT) levels, which may contribute to its inhibitory effects on prostate cancer and BPH. The active ingredient in enteric-coated TRPM8 agonist D-3263 hydrochloride binds to and activates TRPM8, which may result in an increase in calcium and sodium entry; the disruption of calcium and sodium homeostasis; and the induction of cell death in TRPM8-expressing tumor cells." TRPM8 deficiency in macrophages have shown defective phagocytosis and increased motility. Basically, these white blood cells, that are not stimulated properly by a TRPM8 ligand, tend to wonder around without eating any bacteria. This also can exacerbate inflammatory bowel disease. TRPM8 receptors (better defined as a channel) creates a flow of calcium into a cell. There is a receptor on TRPM8 that CBD, and other ligand, to regulate the calcium flow into a cell. If the receptor is not stimulated correctly, or if a bad ligand like cholesterol interacts with TRPM8, the inflow of calcium into the cell will be erratic. Researches have hypothesized that increased cholesterol can make the lipid raft of the cell thicker and less fluid, while TRM8 ligands (such as geraniol) will enhance the membrane fluidity. Selective TRPM8 agonist (D-3263 hydrochloride) might have more side effects compared to whole cannabis oil which interacts with many receptors. Mu Opioid Receptor Ligand One of the methods why CBD can relieve pain is its ability to bind to the same receptor as morphine. CBD may also help relieve the addiction to opiates. Cannabinoids: CBD Pharmaceutical drug: Morphine There are 5 opiate receptors. So far, CBD has been identified to interact with the Mu Opioid Receptor. The breakdown of opiate receptors are: Mu Opioid Receptor (Morphine) Kappa 1 (Dynorphin A, U50, 488H) Kappa 2 (Ethylketocyclazocine) Kappa 3 (Naloxone, benzoylhydrazone, Levorphanol) Delta (Enkephalin, DPDPE) The Mu Opioid Receptor has been identified to be the only receptor that can have a physical addiction to, which is why morphine can be highly addictive! Morphine can also make people stop breathing. CBD may be able to help those addicted to opiates by helping with the pain, and help relieve the physical addiction to opiates by going to the same receptor. 5-HT1A agonist Cannabinoids: CBD Terpenes: d-limonene Pharmaceutical drugs: SSRI fluvoxamine (Luvox CR) fluoxetine (Sarafem, Prozac, Selfemra, Rapiflux) paroxetine (Pexeva, Paxil, Brisdelle, sertraline, Zoloft) 5-HT1A medications are commonly used for treating depression. 5HT-1A are also known as a serotonin receptor. This is one of the receptors that CBD will interact with. Even the terpene, d-limonene, has been found to increase serotonin and dopamine. COX-2 Inhibitor Cannabinoids: CBDA, THCA (weaker than CBDA) Pharmaceutical drugs: NSAIDS (ibuprofin, naproxen, etc), Celebrex CBDA and THCA both act as a COX-2 inhibitor. This is how over the counter NSAIDS alleviate pain. NSAIDS will also inhibit COX-1, and this decreases the mucus lining in our stomachs which can lead to ulcers. Celebrex will selectively inhibit COX-2 without inhibiting COX-1 (or at least to a lesser extent). CBDA and THCA is definitely a much better choice! FAAH Inhibition Cannabinoids: CBD Pharmaceutical drugs: BIA 10-2474 (failed) FAAH inhibitors may be useful in treating colitis, inflammatory bowel disease, anxiety, depression, and pain. The FAAH inhibitor, BIA 10-2474, was developed because they are able to increase the concentration of endocannabinoids. Phase 1 clinical trials were done in France which resulted in 1 death, and 5 other people were brain damaged. The pharmaceutical companies may have given up on FAAH inhibitors. CBD will safely inhibit FAAH, and many people with inflammatory bowel disease get relief even with THC. Inhibiting FAAH has has also shown to decrease hyperactive intestines, which is often a problem in Irritable Bowel Syndrome. GPR55 antagonist Cannabinoids: CBD GPR55 antagonist has been identified as a new treatment for pancreatic ductal adenocarcinoma (PDAC). It also was shown to be effective in inhibiting the metastasis with colon and breast cancer. CBD has been the only cannabinoid identified so far to act as a GPR55 antagonist. CBD was also used in combination with gemcitabine (in vivo and in vitro), and was found to increase the effectives of that chemotherapy drug. Gemcitabine is currently used to treat: Ovarian Cancer, Breast Cancer, Non-Smaill Cell Lung Cancer, Pancreatic Cancer. Phospholipase A2 modulator Cannabinoids: CBD, CBG Phospholipase A2 is an enzyme that is produced in the pancreas. Its normal role is in response to eating food and infections. Some people have an altered gene expression, or some infections that can change how Phospholipase A2 acts in the body. Phospholipase A2 genetic disorders: classic infantile neuroaxonal dystrophy atypical neuroaxonal dystrophy of childhood-onset PLA2G6-related dystonia-parkinsonism with late onset in adulthood Inflammatory metabolic diseases include: atherosclerosis hyperlipidemia obesity diabetes Phospholipase A2 is also expressed in the lungs, and studies are being done on its effectiveness in treating Meconium aspiration syndrome Rheumatoid Arthritis had mixed results with Phospholipase A2 modulators. CBD and CBG may help with the above disorders by correcting the enzyme activity of Phospholipase A2. 15-Lipoxygenase inhibitor Cannabinoids: CBD 15-Lipoxygenase is a key enzyme involved in fatty acid metabolism that oxidizes unsaturated fatty acids. That enzyme is the beginning of a chain of interactions. Think of 15-Lipoxygenase as the start of a pathway. the end of the pathway is the DNA of the cell. One function of this DNA expression is to produce mucus in our airways. Smoking causes an increased expression of 15-Lipoxygenase. This is associated with Interleukin-4 driven inflammation and mucus hypersecretion. Asthma and COPD both have Up-regulation of 15-Lipoxygenase. So far, CBD has been the only cannabinoid to act as a 15-Lipoxygenase inhibitor 5-Lipoxygenase inhibitor Cannabinoids: CBD Pharmaceutical drug: Zileuton 5-Lipoxygenase is an enzyme responsible for creating leukotrienes. This has been already useful in treating asthma. There is further research going on for using 5-Lipoxygenase inhibitors for treating athersclerosis. 5-Lipoxygenase may also be one of the factors in cancer formation (tumorigenesis). Zileuton Extended-Release Tablets is indicated for the prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older. Zileuton is a 5-Lipoxygenase inhibitor and blocks leukotrienes. CBD has been the only cannabinoid found to act as a 5-Lipoxygenase inhibitor. T-type Ca2+ channel inhibitor Cannabinoids: CBD Pharmaceutical drug: Posicor (Mibefradil) T-type calcium channels are expressed in many diverse tissues, including neuronal, cardiovascular, and endocrine. T-type calcium channels are known to play roles in the development, maintenance, and repair of these tissues but have also been implicated in disease when not properly regulated. T-type calcium channel inhibitors are currently used in treating angina, high blood pressure, and preventing cardiac cell hypertrophy. It has also been used in conjunction with the chemotherapeutic agent Carboplatin. T-type calcium channel inhibitors helps sensitize ovarian cancer to Carboplatin. Regulator of intracellular calcium Cannabinoids: CBD Irregular calcium flow within certain neurons can cause seizures, among other problems. Calcium flow within a cell's mitochondria can lead to several neurodegenerative diseases such as Huntington's disease and Friedreich's ataxia. CBD has the benefit of regulating intracellular calcium proving that CBD is a potent neuroprotectant, as well as having anti-epileptic properties. Suppressor of tryptophan degradation Cannabinoids: CBD Pharmaceutical drugs: Over the counter supplements (i.e. L-Tryptophan) Tryptophan is an essential amino acid that our body needs, and enzymes in our body will break tryptophan down. Low levels of tryptophan have shown impairments in learning on visual discrimination and memory retrieval, episodic memory, stimulus-reward learning, and cognitive flexibility, among other cognitive processes. Low tryptophan levels have also been responsible for anger, hostility, aggression, problems with impulse control, and even ADHD. Tryptophan has been used for a broad spectrum of clinical applications, such as treatment of pain, insomnia, depression, seasonal affective disorder, bulimia, premenstrual dysphoric disorder, attention deficit/ hyperactivity disorder, and chronic fatigue You will still need to get tryptophan from food, and CBD will help keep the tryptophan levels up and for a longer period of time. PPARy agonist Cannabinoids: CBD Pharmaceutical drugs: pioglitazone (Actos), rosiglitazone (Avandia) PPARy agonist are currently being used to treat Diabetes. The above pharmaceutical drugs have been found to make heart failure worse. Those drugs lower blood sugar by reducing circulating fat in the blood and storing the fat into peripheral tissues. Of course, that will lead to an increase in body fat. Those drugs are usually used in combination with metformin or sulphonylureas. Using a combination of CBD and THC, like a 1:1 ratio, can have a much better effect on lowering blood sugar without the side effects of pharmaceuticals. Adenosine uptake competitive inhibitor Cannabinoids: CBD Elevating extracellular adenosine levels have shown protective or ameliorating effects in ischemic cardiac and cerebral injury, organ transplantation, seizures, thrombosis, insomnia, pain, and inflammatory diseases. Our body produces more extracellular adenosine under several adverse conditions, including ischemia, trauma, stress, seizures and inflammation. Our cells take up the adenosine quickly, and the benefits of adenosine become lost. CBD helps keep more extracellular adenosine by blocking its uptake into cells. This can also have antiarrythmic actions, and increase blood flow through the coronary arteries. Doctors sometimes use intravenous adenosine for chemical cardioversion. Such as restoring normal sinus rhythm from Super Ventricular Tachycardia. Intravenous adenosine does actually stop the heart for a second to try and "reboot" the heart into a normal rhythm. Acetylcholinesterase inhibitor Cannabinoids and terpenes: This will take a combination of a-Pinene and CBD/THC Pharmaceuticals: donepezil (Aricept), tacrine (Cognex), galantamine (Razadyne, Reminyl), rivastigmine (Exelon), donepezil / memantine (Namzaric) Acetylcholinesterase inhibitors are used in treating dementia and Alzheimer's by helping with short term memory recall. A combination of a-Pinene and either CBD or THC will act as an Acetylcholinesterase inhibitor. Many marijuana users have found that strains high in a-Pinene can sometimes make people minds race too much, but this may be beneficial for dementia. Elderly with dementia would more likely respond better with CBD with a-Pinene than psychoactive THC. Since acetylcholine goes to ACH/Nicotinic receptors. It is possible that people addicted to nicotine may find that smoking a strain rich in a-Pinene might help reduce nicotine cravings. The same receptors are being activated. GABA Cannabinoid and Terpene: CBG with Phytol Pharmaceuticals: Benzodiazepines (lorazapam, diazapam) GABA is a neurotransmitter that is often linked to a happy feeling or a calming effect. Over the counter GABA supplements are often used for: Improve mood Relieve anxiety Improve sleep Help with premenstrual syndrome (PMS) Treat attention deficit hyperactivity disorder Benzodiazapines go to the same receptor as GABA, but can have much different side effects than a GABA neurotransmitter attaching to a GABA receptor. A combination of CBG and the terpene, Phytol, has been found to stop the enzyme SSADH from breaking down GABA. This will increase GABA levels, restoring that calming effect.

Beta Secretase Inhibitors

 

 

Terpenes: Geranyl acetone, Camphor, Fenchone,

 

Beta secretase 1 (BACE1) inhibitors are considered a leading treatment for treating Alzheimer's disease. They are still under going clinical trials. Early in Alzheimer's disease, the β-secretase (BACE1) enzyme required for the production of the neurotoxic β-amyloid. Beta secretase 1 (BACE1) inhibitors will reduce the formation of the neurotoxic β-amyloid (Aβ) peptide.

 

So far, cannabinoids help Alzheimer's disease in other ways. A few terpenes have been found to act as beta secretase 1 (BACE1) inhibitors.

 

The actual data for the terpenes are as follows, most potent one first:

 

The terpene data was taken from: Marumoto, Shinsuke & Okuno, Yoshiharu & Miyazawa, Mitsuo. (2017). Inhibition of β-Secretase Activity by Monoterpenes, Sesquiterpenes, and C13 Norisoprenoids. Journal of oleo science. 66. 10.5650/jos.ess16188. https://www.jstage.jst.go.jp/article/jos/66/8/66_ess16188/_article

 

The rest of the sources are at the bottom of this webpage

CB1 & CB2 Cannabinoids: CBD is a CB2 inverse agonist, and an antogonist of CB1/CB2 agonist CBG is a CB1/CB2 partial agonist Delta 9 THC is a CB1/CB2 partial agonist Delta 9 THCV is a CB1 antagonist, and a CB2 partial agonist Pharmaceutical drugs: Rimonabant CB1 receptors were generally known for the "getting high" receptor, and the CB2 receptor was the immune receptor. CB1 and CB2 do so much more than that! CB1 receptors inhibit release of excitatory and inhibitory neurotransmitters such as acetylcholine noradrenaline GABA glutamate dopamine CB2 receptors are more associated with the immune system. CB2 activation is an important role in cell biology, and act as an immunomodulator. CB2 helps with B cell differentiation by acting as a promoter for DNA transcription (exon 2 in humans). In the central nervous system, microglia also express a CB2 receptor. Microglia are important for our brain health, and if microglia are not stimulated properly, it can lead to Alzheimer's disease or dementia. The CB2 expression of macrophages also are involved in atherosclerosis. Oxidized LDL cholesterol are eaten by macrophages, and the white blood cell dies leaving plaque. Cannabinoids have been shown to reduce the progression of established lesions. The pharmaceutical companies have attempted to make an inverse agonist for the CB1 receptor called Rimonabant. This was developed as an anorectic anti-obesity drug. It never reached the USA, but was withdrawn in the rest of the world in 2008 due to severe psychiatric side effects. Exocannabinoids are less selective in targeting CB1 and CB2 receptors as compared to endocannabinoids (anandamide and 2-AG). This is due to the nature of endocannabinoid signaling. Overactive immune cells (autoimmune disorders) have shown T-cells to be down-regulated with CB2 activation. The cannabinoid system regulates our immune system into homeostasis. TRPA1 Sources Takaishi, Masayuki et al. “1,8-cineole, a TRPM8 agonist, is a novel natural antagonist of human TRPA1” Molecular pain vol. 8 86. 29 Nov. 2012, doi:10.1186/1744-8069-8-86 Guimaraes MZP, Jordt SE. TRPA1 : A Sensory Channel of Many Talents. In: Liedtke WB, Heller S, editors. TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades. Boca Raton (FL): CRC Press/Taylor & Francis; 2007. Chapter 11. Akopian AN1, Ruparel NB, Patwardhan A, Hargreaves KM. Cannabinoids desensitize capsaicin and mustard oil responses in sensory neurons via TRPA1 activation. J Neurosci. 2008 Jan 30;28(5):1064-75. doi: 10.1523/JNEUROSCI.1565-06.2008. Bautista DM1, Jordt SE, Nikai T, Tsuruda PR, Read AJ, Poblete J, Yamoah EN, Basbaum AI, Julius D. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents.Cell. 2006 Mar 24;124(6):1269-82. Koivisto A1, Chapman H, Jalava N, Korjamo T, Saarnilehto M, Lindstedt K, Pertovaara A. TRPA1: a transducer and amplifier of pain and inflammation. Basic Clin Pharmacol Toxicol. 2014 Jan;114(1):50-5. doi: 10.1111/bcpt.12138. Epub 2013 Oct 7. Izzo, Angelo A. Et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in pharmacological sciences. Volume 30, Issue 10, October 2009, Pages 515-527. Website no author: http://algomedix.com/product-pipeline/trpa1-for-pain/ TRPV1 Sources Rosenbaum, Tamara; Simon, Sidney A. TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades. Chapter 5TRPV1 Receptors and Signal Transduction Boca Raton (FL): CRC Press/Taylor & Francis; 2007. Costa, B., Giagnoni, G., Franke, C., Trovato, A. E., & Colleoni, M. (2001). Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation. British journal of pharmacology, 143(2), 247-50. Jara-Oseguera, A., Simon, S. A., & Rosenbaum, T. (2008). TRPV1: on the road to pain relief. Current molecular pharmacology, 1(3), 255-69. Izzo, Angelo A. Et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in pharmacological sciences. Volume 30, Issue 10, October 2009, Pages 515-527 Jansson, Erik T. Et al. Effect of Cholesterol on the Pore Dilation of TRPV1 Molecular pain. 9. 1. 10.1186/1744-8069-9-1. Vigna, Steven R. “5-Aminosalicylic Acid Inhibits Acute Clostridium difficile Toxin A-Induced Colitis in Rats” International journal of inflammation vol. 2014 (2014): 389621. Melo Júnior, J.M.A., Damasceno, M.B.M.V., Santos, S.A.A.R. et al. Acute and neuropathic orofacial antinociceptive effect of eucalyptol Inflammopharmacol (2017) 25: 247. https://doi.org/10.1007/s10787-017-0324-5 Tsuji, Fumio and Hiroyuki Aono. “Role of transient receptor potential vanilloid 1 in inflammation and autoimmune diseases” Pharmaceuticals (Basel, Switzerland) vol. 5,8 837-52. 17 Aug. 2012, doi:10.3390/ph5080837 Vigna, Steven R. “5-Aminosalicylic Acid Inhibits Acute Clostridium difficile Toxin A-Induced Colitis in Rats” International journal of inflammation vol. 2014 (2014): 389621. Modulation of Human Neutrophil Responses by the Essential Oils from Ferula akitschkensis and Their Constituents Igor A. Schepetkin, Svetlana V. Kushnarenko, Gulmira Özek, Liliya N. Kirpotina, Pritam Sinharoy, Gulzhakhan A. Utegenova, Karime T. Abidkulova, Temel Özek, Kemal Hüsnü Can Başer, Anastasia R. Kovrizhina, Andrei I. Khlebnikov, Derek S. Damron, and Mark T. Quinn Journal of Agricultural and Food Chemistry 2016 64 (38), 7156-7170 DOI: 10.1021/acs.jafc.6b03205 Premkumar, Louis S. “Transient receptor potential channels as targets for phytochemicals” ACS chemical neuroscience vol. 5,11 (2014): 1117-30. Website no author: https://www.drugs.com/fda-alerts/492-231.html Website no author: https://www.drugs.com/cdi/zostrix-capsaicin-cream-gel-liquid-and-lotion.html Website no author: https://www.drugs.com/mtm/trixaicin.html Website no author: https://www.drugs.com/cdi/axsain.html TRPV2 Sources Elbaz M, Ahirwar D, Xiaoli Z, Zhou X, Lustberg M, Nasser MW, Shilo K, Ganju RK. TRPV2 is a novel biomarker and therapeutic target in triple negative breast cancer. V'yacheslav Lehen'kyi, Natalia Prevarskaya. TRPV2 (transient receptor potential cation channel, subfamily V, member 2) Inserm, U-1003, Universite des Sciences et Technologies de Lille (USTL), Villeneuve d'Ascq, France. March 2012 Izzo, Angelo A. Et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in pharmacological sciences. Volume 30, Issue 10, October 2009, Pages 515-527 Hisanaga, Etsuko et al. “Regulation of calcium-permeable TRPV2 channel by insulin in pancreatic beta-cells” Diabetes vol. 58,1 (2009): 174-84. Lin, Yi and Zhongjie Sun. “Antiaging gene Klotho enhances glucose-induced insulin secretion by up-regulating plasma membrane levels of TRPV2 in MIN6 β-cells” Endocrinology vol. 153,7 (2012): 3029-39. Website no author: http://www.proteinatlas.org/ENSG00000187688-TRPV2/tissue Website no author: https://www.selleckchem.com/products/probenecid-benemid.html Website no author: https://www.tocris.com/pharmacology/trpv Website no author: http://atlasgeneticsoncology.org/Genes/TRPV2ID45817ch17p11.html TRPM8 Sources Dussor, Greg PhD Cao, Yu‐Qing PhD. Headache: journal of head and face pain. TRPM8 and Migraine. Volume 56, Issue 9 October 2016 Pages 1406-1417 Weyer, Andy D. Lehto, Sonya G. Development of TRPM8 Antagonists to Treat Chronic Pain and Migraine. Pharmaceuticals 2017, 10, 37; doi:10.3390/ph10020037 Cruz Morenilla-Palao, María Pertusa, Víctor Meseguer, Hugo Cabedo, Félix Viana. Lipid Raft Segregation Modulates TRPM8 Channel Activity. Journal of Biological Chemistry. January 27, 2009 doi: 10.1074/jbc.M807228200 Diana M. Bautista, Jan Siemens, Joshua M. Glazer, Pamela R. Tsuruda, Allan I. Basbaum, Cheryl L. Stucky, Sven-Eric Jordt, David Julius. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature: International journal of science.448, pages 204–208 (12 July 2007) Izzo, Angelo A. Et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in pharmacological sciences. Volume 30, Issue 10, October 2009, Pages 515-527 Sherkheli, Azhar & Vogt-Eisele, Angela & Bura, Daniel & R. Beltrán Márques, Leopoldo & Gisselmann, Günter & Hatt, Hanns. (2010). Characterization of Selective TRPM8 Ligands and their Structure Activity Response (S.A.R.) Relationship. Journal of Pharmacy and Pharmaceutical Sciences, v.13, 242-253 (2010). 13. 10.18433/J3N88N. https://www.cancer.gov/publications/dictionaries/cancer-drug/def/enteric-coated-trpm8-agonist-d-3263-hydrochloride
 Takaishi, Masayuki et al. “1,8-cineole, a TRPM8 agonist, is a novel natural antagonist of human TRPA1” Molecular pain vol. 8 86. 29 Nov. 2012, doi:10.1186/1744-8069-8-86 M Khalil, A Babes, R Lakra, S Försch, P W Reeh, S Wirtz, C Becker, M F Neurath & M A Engel.Transient receptor potential melastatin 8 ion channel in macrophages modulates colitis through a balance-shift in TNF-alpha and interleukin-10 production. Mucosal Immunology volume 9, pages 1500–1513 (2016) McKemy DD. TRPM8: The Cold and Menthol Receptor. In: Liedtke WB, Heller S, editors. TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades. Boca Raton (FL): CRC Press/Taylor & Francis; 2007. Chapter 13. Available from: https://www.ncbi.nlm.nih.gov/books/NBK5238/ Yee, Nelson S. “Roles of TRPM8 Ion Channels in Cancer: Proliferation, Survival, and Invasion” Cancers vol. 7,4 2134-46. 23 Oct. 2015, doi:10.3390/cancers7040882 Sources for Mu Opioid Receptor Pasternak, Gavril. Pan, Ying-Xian. Mu opioid receptors in pain management. Acta Anaesthesiologica Taiwanica Volume 49, Issue 1, March 2011, Pages 21-25 Contet, Candice. Kieffer, Brigitte L. Befort, Katia. Mu opioid receptor: a gateway to drug addiction. Current Opinion in Neurobiology Volume 14, Issue 3, June 2004, Pages 370-378 Pasternak, Gavril W and Ying-Xian Pan. “Mu opioids and their receptors: evolution of a concept” Pharmacological reviews vol. 65,4 1257-317. Oct. 2013, doi:10.1124/pr.112.007138 Izzo, Angelo A. Et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in pharmacological sciences. Volume 30, Issue 10, October 2009, Pages 515-527 Sources for 5HT1-A Celada, Pau et al. “The therapeutic role of 5-HT1A and 5-HT2A receptors in depression” Journal of psychiatry & neuroscience : JPN vol. 29,4 (2004): 252-65. Blessing, Esther M et al. “Cannabidiol as a Potential Treatment for Anxiety Disorders” Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics vol. 12,4 (2015): 825-36. Website no author https://www.drugs.com/drug-class/ssri-antidepressants.html https://www.drugs.com/drug-class/ssri-antidepressants.html Yun, Jaesuk. (2014). Limonene inhibits methamphetamine-induced locomotor activity via regulation of 5-HT neuronal function and dopamine release. Phytomedicine : international journal of phytotherapy and phytopharmacology. 21. . 10.1016/j.phymed.2013.12.004. http://pdring.com/parkinsons-disease-drugs-medicines-overdose-symptoms.htm https://www.mayoclinic.org/diseases-conditions/serotonin-syndrome/symptoms-causes/syc-20354758 Lisa Wise-Faberowski, Susan Black, in Complications in Anesthesia (Second Edition), 2007 Izzo, Angelo A. Et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in pharmacological sciences. Volume 30, Issue 10, October 2009, Pages 515-527 Sources for COX-2 inhibition Izzo, Angelo A. Et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in pharmacological sciences. Volume 30, Issue 10, October 2009, Pages 515-527 Fookes, C. COX-2 Inhibitors. BPharm. Jul 3, 2018. Taken from https://www.drugs.com/drug-class/cox-2-inhibitors.html on 5/25/2019 Sources for FAAH Inhibition Mallet, Christophe. Dubray, Claude. Dualé, Christian. Int J Clin Pharmacol Ther. FAAH inhibitors in the limelight, but regrettably 2016 Jul; 54(7): 498–501. Published online 2016 May 18. doi: 10.5414/CP202687 PMID: 27191771 Kaur, R., Sidhu, P., & Singh, S. (2016). What failed BIA 10-2474 Phase I clinical trial? Global speculations and recommendations for future Phase I trials. Journal of pharmacology & pharmacotherapeutics, 7(3), 120-6. Blamont, Matthias. Reuters Paris. French drug trial disaster leaves one brain dead, five injured. World News January 15, 2016 De Filippis, D. , Iuvone, T. , D'amico, A. , Esposito, G. , Steardo, L. , Herman, A. G., Pelckmans, P. A., De Winter, B. Y. and De Man, J. G. (2008), Effect of cannabidiol on sepsis‐induced motility disturbances in mice: involvement of CB1 receptors and fatty acid amide hydrolase. Neurogastroenterology & Motility, 20: 919-927. doi:10.1111/j.1365-2982.2008.01114.x Capasso, R., Borrelli, F., Aviello, G., Romano, B., Scalisi, C., Capasso, F., & Izzo, A. A. (2008). Cannabidiol, extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice. British journal of pharmacology, 154(5), 1001-8. Ahn, K., Johnson, D. S., & Cravatt, B. F. (2009). Fatty acid amide hydrolase as a potential therapeutic target for the treatment of pain and CNS disorders. Expert opinion on drug discovery, 4(7), 763-784. Kristina L. Leinwand, Mark E. Gerich, Edward J. Hoffenberg, Colm B. Collins; Manipulation of the Endocannabinoid System in Colitis: A Comprehensive Review, Inflammatory Bowel Diseases, Volume 23, Issue 2, 1 February 2017, Pages 192–199 Izzo, Angelo A. Et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in pharmacological sciences. Volume 30, Issue 10, October 2009, Pages 515-527 Sources for GPR55 R. Ferro, A. Adamska, R. Lattanzio, I. Mavrommati, C. E. Edling, S. A. Arifin, C. A. Fyffe, G. Sala, L. Sacchetto, G. Chiorino, V. De Laurenzi, M. Piantelli, O. J. Sansom, T. Maffucci & M. Falasca. GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine. Oncogene volume 37, pages 6368–6382 (2018). Izzo, Angelo A. Et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in pharmacological sciences. Volume 30, Issue 10, October 2009, Pages 515-527 https://www.drugs.com/pro/gemcitabine.html Sources for Phospholipase A2 Magolda, R. Trzaskos, J. Therapeutic Areas II: Cancer, Infectious Diseases, Inflammation & Immunology and Dermatology in Comprehensive Medicinal Chemistry II, 2007 Daniele De Luca, Angelo Minucci, Domenico Tripodi, Marco Piastra, Domenico Pietrini, Cecilia Zuppi, Giorgio Conti, Virgilio P. Carnielli, Ettore Capoluongo. Role of distinct phospholipases A2 and their modulators in meconium aspiration syndrome in human neonates. Intensive Care Medicine. July 2011, Volume 37, Issue 7, pp 1158–1165 Hui, David Y. “Phospholipase A(2) enzymes in metabolic and cardiovascular diseases” Current opinion in lipidology vol. 23,3 (2012): 235-40. David Y. Hui. Group 1B phospholipase A2 in metabolic and inflammatory disease modulation. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 9 July 2018 Izzo, Angelo A. Et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in pharmacological sciences. Volume 30, Issue 10, October 2009, Pages 515-527 Website Dr Daniel J Bell and Dr Samir Sari Omar et al. Phospholipase A2 associated neurodegeneration. Taken from https://radiopaedia.org/articles/phospholipase-a2-associated-neurodegeneration on 3/18/2019. Sources for 15-Lipoxygenase inhibitor Jinming Zhao, Valerie B. O'Donnell, Silvana Balzar, Claudette M. St. Croix, John B. Trudeau, and Sally E. Wenzel. 15-Lipoxygenase 1 interacts with phosphatidylethanolamine-binding protein to regulate MAPK signaling in human airway epithelial cells. PNAS August 23, 2011 108 (34) 14246-14251 Pascal Chanez , Caroline Bonnans , Claude Chavis , and Isabelle Vachier. 15-Lipoxygenase: A Janus Enzyme? American Journal of Respiratory Cell and Molecular Biology. Vol. 27, No. 6 | Dec 01, 2002 Izzo, Angelo A. Et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in pharmacological sciences. Volume 30, Issue 10, October 2009, Pages 515-527 Sources for 15-Lipoxygenase inhibitor Jinming Zhao, Valerie B. O'Donnell, Silvana Balzar, Claudette M. St. Croix, John B. Trudeau, and Sally E. Wenzel. 15-Lipoxygenase 1 interacts with phosphatidylethanolamine-binding protein to regulate MAPK signaling in human airway epithelial cells. PNAS August 23, 2011 108 (34) 14246-14251 Pascal Chanez , Caroline Bonnans , Claude Chavis , and Isabelle Vachier. 15-Lipoxygenase: A Janus Enzyme? American Journal of Respiratory Cell and Molecular Biology. Vol. 27, No. 6 | Dec 01, 2002 Izzo, Angelo A. Et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in pharmacological sciences. Volume 30, Issue 10, October 2009, Pages 515-527 Sources for 5-Lipoxygenase inhibitor https://www.drugs.com/mtm/zileuton.html Rossi, A et al. “The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages” British journal of pharmacology vol. 161,3 (2010): 555-70. Rådmark, Olof and Bengt Samuelsson. “5-Lipoxygenase: mechanisms of regulation” Journal of lipid research vol. 50 Suppl,Suppl (2009): S40-5. Izzo, Angelo A. Et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in pharmacological sciences. Volume 30, Issue 10, October 2009, Pages 515-527 Sources for T-type Ca2+ channel inhibitor Barbara Dziegielewska, Eli V. Casarez, Wesley Z. Yang, Lloyd S. Gray, Jaroslaw Dziegielewski and Jill K. Slack-Davis. T-Type Ca2+ Channel Inhibition Sensitizes Ovarian Cancer to Carboplatin. Cancer Biology and Signal Transduction. DOI:10.1158/1535-7163.MCT-15-0456 Published March 2016 Kopecky, Benjamin J et al. “T-type calcium channel blockers as neuroprotective agents” Pflugers Archiv : European journal of physiology vol. 466,4 (2014): 757-65. https://www.drugs.com/ingredient/mibefradil.html Hye Hong, Da & Yang, Dongki & Choi, Il-Whan & Kyoung Son, Youn & Jung, Won-Kyo & Kim, Dae-Joong & Han, Jin & Hun Na, Sung & Sun Park, Won. (2012). The T-type Ca2+ Channel Inhibitor Mibefradil Inhibits Voltage-Dependent K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells. Journal of pharmacological sciences. 120. 10.1254/jphs.12104FP. Izzo, Angelo A. Et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in pharmacological sciences. Volume 30, Issue 10, October 2009, Pages 515-527 Sources for Intracelluar calcium regulation Duncan Ryan, Alison J. Drysdale, Carlos Lafourcade, Roger G. Pertwee, Bettina Platt. Cannabidiol Targets Mitochondria to Regulate Intracellular Ca2+ Levels. Journal of Neuroscience 18 February 2009, 29 (7) 2053-2063; DOI: 10.1523/JNEUROSCI.4212-08.2009 Drysdale AJ1, Ryan D, Pertwee RG, Platt B. Cannabidiol-induced intracellular Ca2+ elevations in hippocampal cells. Neuropharmacology. 2006 Apr;50(5):621-31. Epub 2005 Dec 28. Izzo, Angelo A. Et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in pharmacological sciences. Volume 30, Issue 10, October 2009, Pages 515-527 Sources for suppression of tryptophan degradation Richard, Dawn M et al. “L-Tryptophan: Basic Metabolic Functions, Behavioral Research and Therapeutic Indications” International journal of tryptophan research : IJTR vol. 2 (2009): 45-60. Jenkins TA1, Nguyen JC2, Polglaze KE3, Bertrand PP4,5.Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis. Nutrients. 2016 Jan 20;8(1). pii: E56. doi: 10.3390/nu8010056. Strasser B1, Gostner JM, Fuchs D. Mood, food, and cognition: role of tryptophan and serotonin. Curr Opin Clin Nutr Metab Care. 2016 Jan;19(1):55-61. doi: 10.1097/MCO.0000000000000237. Izzo, Angelo A. Et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in pharmacological sciences. Volume 30, Issue 10, October 2009, Pages 515-527 Sources for PPARy agonist website https://www.sciencedirect.com/topics/neuroscience/ppar-agonist CHRISTOPHER B. GUEST,, GREGORY G. FREUND, et all. Peroxisome Proliferator-activated Receptor. Obesity and Immunity. Psychoneuroimmunology (Fourth Edition), 2007 Izzo, Angelo A. Et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in pharmacological sciences. Volume 30, Issue 10, October 2009, Pages 515-527 https://www.drugs.com/drug-class/thiazolidinediones.html Sources for Adenosine uptake competitive inhibitor Noji, Tohru & Karasawa, Akira & Kusaka, Hideaki. (2004). Adenosine uptake inhibitors. European journal of pharmacology. 495. 1-16. 10.1016/j.ejphar.2004.05.003. Izzo, Angelo A. Et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in pharmacological sciences. Volume 30, Issue 10, October 2009, Pages 515-527 https://www.drugs.com/ppa/adenosine.html Sources for Acetylcholinesterase inhibitor Colović, Mirjana B et al. “Acetylcholinesterase inhibitors: pharmacology and toxicology” Current neuropharmacology vol. 11,3 (2013): 315-35. Izzo, Angelo A. Et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in pharmacological sciences. Volume 30, Issue 10, October 2009, Pages 515-527 Russo, Ethan B. “Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects” British journal of pharmacology vol. 163,7 (2011): 1344-64. Website no author. https://www.drugs.com/drug-class/cholinesterase-inhibitors.html Sources for GABA Bang MH, Choi SY, Jang TO, Kim SK, Kwon OS, Kang TC, et al. Phytol, SSADH inhibitory diterpenoid of Lactuca sativa. Arch Pharm Res. 2002;25:643–646. Russo, Ethan B. “Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects” British journal of pharmacology vol. 163,7 (2011): 1344-64. Website no author. https://www.drugs.com/drug-class/benzodiazepines.html Website no author. https://www.webmd.com/vitamins-and-supplements/gaba-uses-and-risks Sources for Beta secretase 1 (BACE1) inhibitors https://www.elsevier.com/about/press-releases/research-and-journals/beta-secretase-inhibitors-to-treat-alzheimers-disease Beta Secretase Inhibitors to Treat Alzheimer’s Disease A note of caution from a new study in Biological Psychiatry April 2, 2015 Menting, Kelly Willemijn and Jurgen A H R Claassen. “β-secretase inhibitor; a promising novel therapeutic drug in Alzheimer's disease” Frontiers in aging neuroscience vol. 6 165. 21 Jul. 2014, doi:10.3389/fnagi.2014.00165 Vassar, Robert. “BACE1 inhibitor drugs in clinical trials for Alzheimer's disease” Alzheimer's research & therapy vol. 6,9 89. 24 Dec. 2014, doi:10.1186/s13195-014-0089-7 Marumoto, Shinsuke & Okuno, Yoshiharu & Miyazawa, Mitsuo. (2017). Inhibition of β-Secretase Activity by Monoterpenes, Sesquiterpenes, and C13 Norisoprenoids. Journal of oleo science. 66. 10.5650/jos.ess16188. Sources for CB1 and CB2 Sherwood, Tracy A et al. “Identification of transcription start sites and preferential expression of select CB2 transcripts in mouse and human B lymphocytes” Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology vol. 4,4 (2009): 476-88. Pertwee, R G. “The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin” British journal of pharmacology vol. 153,2 (2007): 199-215. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219532/ Izzo, Angelo A. Et al. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in pharmacological sciences. Volume 30, Issue 10, October 2009, Pages 515-527 Freeman-Anderson, Natalie E et al. “Cannabinoid (CB2) receptor deficiency reduces the susceptibility of macrophages to oxidized LDL/oxysterol-induced apoptosis” Journal of lipid research vol. 49,11 (2008): 2338-46. Eisenstein, Toby K and Joseph J Meissler. “Effects of Cannabinoids on T-cell Function and Resistance to Infection” Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology vol. 10,2 (2015): 204-16. Moreira FA1, Crippa JA.The psychiatric side-effects of rimonabant. Braz J Psychiatry. 2009 Jun;31(2):145-53. Home
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