Your Cannabis CBD:THC Ratio
A Guide to Precision Dosing for Health and Wellness
by Uwe Blesching, Ph.D.
Endnotes
Endnotes
Introduction: Why Cannabis Works
1 Maureen Dowd. “Don’t Harsh Our Mellow, Dude,” Opinion, Op-Ed Columnist, The New York Times, June 3, 2014.
Chapter 1: Top 10 Reasons People Seek Medical Care
1 Harder, Ben (August 1, 2015). “Best Hospitals: 2016-2017 Best Hospitals Honor Roll and Overview”. U.S. News & World Report.
2 St. Sauver JL, Warner DO, Yawn BP, et al. “Why do patients visit their doctors? Assessing the most prevalent conditions in a defined US population.” Mayo Clinic Proceedings 88.1 (2013): 56–67.
3 As you can see, with a few exceptions like hypertension or diabetes, the list contains families of conditions; to stay within the scope of this book, we selected a single of a number of possible options as examples to explore (see parentheticals).
Chapter 2: Cannabis as a Healing Plant: Confusion and Insight
1 Hanuš LO, Meyer SM, Muñoz E, Taglialatela-Scafati O, Appendino G. Phytocannabinoids: a unified critical inventory. Nat Prod Rep. 2016 Nov 23;33(12):1357-1392.
2 Jones, Huw; Lister, Diane L.; Bower, Mim A.; Leigh, Fiona J.; Smith, Lydia M.; Jones, Martin K. “Approaches and Constraints of Using Existing Landrace Material to Understand Agricultural Spread in Prehistory”. Plant Genetic Resources. Cambridge University Press. Volume 6, Issue 2 August 2008, pp. 98-112.
3 Villa, T., Maxted, N., Scholten, M., & Ford-Lloyd, B. (2005). Defining and identifying crop landraces. Plant Genetic Resources, 3(3), 373-384.
4 Rey AA, Purrio M, Viveros M-P, Lutz B. Biphasic Effects of Cannabinoids in Anxiety Responses: CB1 and GABAB Receptors in the Balance of GABAergic and Glutamatergic Neurotransmission. Neuropsychopharmacology. 2012;37(12):2624-2634.
5 Tompson, G.R., Rosenkrantz, H., Schaeppi, U.H., and Braude, M.C. 1973. “Comparison of acute oral toxicity of cannabinoids in rats, dogs and monkeys.” Toxicol Appl Pharmacol 25:363–72.
6 Gregory T. Carter, Patrick Weydt, Muraco Kyashna-Tocha, and Donald Abrams. 2004 (May). “Medicinal Cannabis: Rational guidelines for Dosing.” IDrugs 7(5):464–70.
7 National Cancer Institute. Cannabis and Cannabinoids (PDQ®) – Health Professional Version. Adverse Effects. https://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq#link/stoc_h2_5
8 Adams IB, Martin BR: Cannabis: pharmacology and toxicology in animals and humans. Addiction 91 (11): 1585-614, 1996.
9 Grotenhermen F, Russo E, eds. Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential. Binghamton, NY: The Haworth Press, 2002.
10 Sutton IR, Daeninck P. Cannabinoids in the management of intractable chemotherapy-induced nausea and vomiting and cancer-related pain. J Support Oncol 4 (10): 531-5, 2006 Nov-Dec.
11 Guzmán M. Cannabinoids: potential anticancer agents. Nat Rev Cancer 3 (10): 745-55, 2003.
12 Panlilio LV, Goldberg SR, Justinova Z. Cannabinoid abuse and addiction: Clinical and preclinical findings. Clin Pharmacol Ther. 2015;97(6):616–627.
13 Daniel M. Perrine, The Chemistry of Mind-Altering Drugs (Washington, DC: American Chemical Society, 1997).
14 James C. Anthony, Lynn A. Warner, and Ronald C. Kessler, “Comparative Epidemiology of Dependence on Tobacco, Alcohol, Controlled Substances, and Inhalants: Basic Findings from the National Comorbidity Survey,” Experimental and Clinical Psychopharmacology 2:3 (1994), 244–68.
15 ProCon.org Medical Marijuana. “Deaths from Marijuana v. 17 FDA-Approved Drugs” (Jan. 1, 1997 to June 30, 2005).” http://medicalmarijuana.procon.org /view.resource.php?resourceID=000145.
16 O’Connell, Thomas J., and Bou-Matar, Ché B. 2007. “Long-term marijuana users seeking medical cannabis in California (2001–2007): Demographics, social characteristics, patterns of cannabis and other drug use of 4,117 applicants.” Harm Reduction Journal 4:16.
17 Hanuš LO, Meyer SM, Muñoz E, Taglialatela-Scafati O, Appendino G. Phytocannabinoids: a unified critical inventory. Nat Prod Rep. 2016 Nov 23;33(12):1357-1392.
Chapter 3: Understanding Cannabis Pathways to Body, Mind, and Emotion
1 Lee, M. S. 1999. Molecular clock calibrations and metazoan divergence dates. J Mol Evol 49:385-91.
2 John M. McPartland Patty Pruitt. Sourcing the Code: Searching for the Evolutionary Origins of Cannabinoid Receptors, Vanilloid Receptors, and Anandamide. Journal of Cannabis Therapeutics, Vol. 2(1) 2002.
3 Piomelli D, et al. Endogenous anandamide has often been implicated in behavioral roles, such as emotion. Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597) CNS Drug Rev. 2006;12:21–38.
4 Diamond LM, Fagundes CP, Butterworth MR. “Attachment style, vagal tone, and empathy during mother–adolescent interactions”. Journal of Research on Adolescence. (2012). 22 (1): 165–184.
5 Allyn C Howlett, Patricia H Reggio, Steven R Childers, Robert E Hampson, Nadine M Ulloa, and Dale G Deutsch. Endocannabinoid tone versus constitutive activity of cannabinoid receptors. Br J Pharmacol. 2011 Aug; 163(7): 1329–1343.
6 Howlett A. C. et al.
7 Howlett A. C. et al.
8 Piomelli D, et al. Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597) CNS Drug Rev. 2006;12:21–38.
9 Varvel SA, Wise LE, Niyuhire F, Cravatt BF, Lichtman AH. Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task. Neuropsychopharmacology. 2007;32:1032–1041.
10 Raichlen, D.A., Foster, A.D., Gerdeman, G.L., Seillier, A., and Giu rida, A. 2012 (Apr 15). “Wired to run: Exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the ‘runner’s high’.” J Exp Biol. 215(Pt 8):1331–36.
11 Trezza, Viviana, and Vanderschuren, Louk J.M.J. 2009 (Jan). “Divergent e ects of anandamide transporter inhibitors with different target selectivity on social play behavior in adolescent rats.” JPET 328(1):343–50.
12 Don Wei, DaYeon Lee, Conor D. Cox, Carley A. Karsten, Olga Peñagarikano, Daniel H. Geschwind, Christine M. Gall, and Daniele Piomelli. Endocannabinoid signaling mediates oxytocin-driven social reward. PNAS November 10, 2015 vol. 112 no. 45 14084-14089.
13 Teniel S. Ramikie, Rita Nyilas, Rebecca J. Bluett, Joyonna C. Gamble-George, Nolan D. Hartley, Ken Mackie, Masahiko Watanabe, István Katona, Sachin Patel. Multiple Mechanistically Distinct Modes of Endocannabinoid Mobilization at Central Amygdala Glutamatergic Synapses. Neuron, Volume 81, Issue 5, 1111-1125.
14 Roger G. Pertwee and Maria Grazia Cascio. The Handbook of Cannabis. Chapter 6. Known Pharmacological Actions of Delta-9-Tetrahydrocannabinol and of Four Other Chemical Constituents of Cannabis that Activate Cannabinoid Receptors. Oxford University Press. 2014.
15 Noyes R Jr, Brunk SF, Baram DA, et al. Analgesic effect of delta-9-tetrahydrocannabinol. J Clin Pharmacol 1975;15:139-43.
16 Noyes R Jr, Brunk SF, Avery DA, et al. The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther 1975;18:84-9.
17 Narang S, Gibson D, Wasan AD, Ross EL, Michna E, Nedeljkovic SS, and Jamison R. Efficacy of Dronabinol as an Adjuvant Treatment for Chronic Pain Patients on Opioid Therapy. J Pain., 2008-03, 9(3):254-264.
18 Holdcroft A, Smith M, Jacklin A, Hodgson H, Smith B, Newton M, and Evans F. Pain relief with oral cannabinoids in familial Mediterranean fever. Anaesthesia. 1997 May;52(5):483-6.
19 Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, and Fallon MT. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manage. 2010 Feb;39(2):167-79.
20 Alexia Blake, Bo Angela Wan,Leila Malek, Carlo DeAngelis, Patrick Diaz, Nicholas Lao, Edward Chow, and Shannon O’Hearn. A selective review of medical cannabis in cancer pain management. Ann Palliat Med. 2017 Dec;6(Suppl 2):S215-S222.
21 Tramèr MR, Carroll D, Campbell FA, Reynolds DJM, Moore RA, McQuay HJ. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ : British Medical Journal. 2001;323(7303):16.
22 T. D. Brisbois, I. H. de Kock, S. M. Watanabe, M. Mirhosseini, D. C. Lamoureux, M. Chasen, N. MacDonald, V. E. Baracos, W. V. Wismer; Delta-9-tetrahydrocannabinol may palliate altered chemosensory perception in cancer patients: results of a randomized, double-blind, placebo-controlled pilot trial, Annals of Oncology, Volume 22, Issue 9, 1 September 2011, Pages 2086–2093.
23 Bedi G, Foltin RW, Gunderson EW, et al. Efficacy and Tolerability of High-Dose Dronabinol Maintenance in HIV-Positive Marijuana Smokers: A Controlled Laboratory Study. Psychopharmacology. 2010;212(4):675-686
24 Haney M, Gunderson EW, Rabkin J, Hart CL, Vosburg SK, Comer SD, and Foltin RW. Dronabinol and marijuana in HIV-positive marijuana smokers. Caloric intake, mood, and sleep. J Acquir Immune Defic Syndr. 2007 Aug 15;45(5):545-54.
25 Müller-Vahl KR, Schneider U, Prevedel H, Theloe K, Kolbe H, Daldrup T, and Emrich HM. Delta 9-tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6-week randomized trial. J Clin Psychiatry. 2003 Apr;64(4):459-65.
26 Spindle TR, Cone EJ, Schlienz NJ, et al. Acute Effects of Smoked and Vaporized Cannabis in Healthy Adults Who Infrequently Use Cannabis: A Crossover Trial [published correction appears in JAMA Netw Open. 2018 Dec 7;1(8):e187241]. JAMA Netw Open. 2018;1(7):e184841
27 Nahas, G. G. (1975) Marijuana: toxicity and tolerance. In Medical Aspects of Drug Abuse (ed. R. W. Richter), pp. 16-36. Baltimore, MD: Harper & Row.
28 Aizpurua-Olaizola, O., Zarandona, I., Ortiz, L., Navarro, P., Etxebarria, N., and Usobiaga, A. (2016) Simultaneous quantification of major cannabinoids and metabolites in human urine and plasma by HPLC-MS/MS and enzyme-alkaline hydrolysis. Drug Test. Analysis, doi: 10.1002/dta.1998.
29 Perez-Reyes M. Marijuana smoking: factors that influence the bioavailability of tetrahydrocannabinol. NIDA Res. Monogr 99. 1990;42-62.
30 Adam Orens, Miles Light, Jacob Rowberry, Jeremy Matsen, and Brian Lewandowski. Prepared for the Colorado Department of Revenue. Marijuana Equivalency in Portion and Dosage. An assessment of physical and pharmacokinetic relationships in marijuana production and consumption in Colorado. August 10, 2015.
31 High Times. The Strongest Strains on Earth. May 2017. Lab testing done by Canna Safe Analytics (Murrieta CA.) Laboratory test used: High-Performance Liquid Chromatography.
32 Carola Rong, Nicole E. Carmona, Yena L. Lee, Renee-Marie Ragguett, Zihang Pan, Joshua D. Rosenblat, Mehala Subramaniapillai, Margarita Shekotikhina, Fahad Almatham, Asem Alageel, Rodrigo Mansur, Roger C. Ho & Roger S. McIntyre. Drug-drug interactions as a result of co-administering Δ9-THC and CBD with other psychotropic agents. Expert Opinion on Drug Safety Vol. 17, Issue 1, 2018.
33 Ayano G. Psychotropic Medications Metabolized by Cytochromes P450 (CYP) 1A2 Enzyme and Relevant Drug Interactions: Review of Articles. Austin J Pharmacol Ther. 2016; 4(2).1085.
34 Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. British Journal of Pharmacology. 2008;153(2):199-215.
35 Leonardo BM Resstel, Rodrigo F Tavares, Sabrina FS Lisboa, Sâmia RL Joca, Fernando MA Corrêa, and Francisco S Guimarães. 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol. 2009 Jan; 156(1): 181–188.
36 Nalivaiko E, Ootsuka Y, Blessing WW. “Activation of 5-HT1A receptors in the medullary raphe reduces cardiovascular changes elicited by acute psychological and inflammatory stresses in rabbits”. Am J Physiol Regul Integr Comp Physiol. (2005). 289 (2): R596–R604.
37 G.A. Kennett , C.T. Dourish 1, G. Curzon. Antidepressant-like action of 5-HT1A agonists and conventional antidepressants in an animal model of depression. European Journal of Pharmacology Volume 134, Issue 3, 24 February 1987, Pages 265-274.
38 Popova, N.K. et al. Involvement of the 5-HT1A and 5-HT1B serotonergic receptor subtypes in sexual arousal in male mice.
39 Tzadok M, Uliel-Siboni S, Linder I, Kramer U, Epstein O, Menascu S, Nissenkorn A, Yosef OB, Hyman E, Granot D, Dor M, Lerman-Sagie T, and Ben-Zeev B. CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience. Seizure. 2016
Feb;35:41-4.
40 Gofshteyn JS, Wilfong A, Devinsky O, Bluvstein J, Charuta J, Ciliberto MA, Laux L, and Marsh ED. Cannabidiol as a Potential Treatment for Febrile Infection-Related Epilepsy Syndrome (FIRES) in the Acute and Chronic Phases. J Child Neurol. 2017 Jan;32(1):35-40.
41 Lippiello P, Balestrini S, Leo A, Coppola A, Citraro R, Elia M, Russo E, and De Sarro G. From Cannabis to Cannabidiol to Treat Epilepsy, Where Are We? Curr Pharm Des. 2016;22(42):6426-6433.
42 Reddy DS, and Golub VM. The Pharmacological Basis of Cannabis Therapy for Epilepsy. J Pharmacol Exp Ther. 2016 Apr;357(1):45-55.
43 Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, Miller I, Flamini R, Wilfong A, Filloux F, Wong M, Tilton N, Bruno P, Bluvstein J, Hedlund J, Kamens R, Maclean J, Nangia S, Singhal NS, Wilson CA, Patel A, Cilio and MR. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016 Mar;15(3):270-8.
44 Orrin Devinsky, Joseph Sullivan, Daniel Friedman, Elizabeth Thiele, Eric Marsh, Linda Laux, Julie Hedlund, Nicole Tilton, Judith Bluvstein and Maria Cilio. Efficacy And Safety of Epidiolex (Cannabidiol) in Children and Young Adults with Treatment-Resistant Epilepsy: Initial Data From an Expanded Access Program. American Epilepsy Society. Annual Meeting Abstracts: View. (Abst. 3.303), 2014.
45 Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker E. Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn Schmiedebergs Arch Pharmacol. 2006 Feb;372(5):354-61.
46 Iuvone T, Esposito G, Esposito R, Santamaria R, Di Rosa M, Izzo AA. Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells. J Neurochem. 2004 Apr;89(1):134-41.
47 Alyssa S.Laun, Zhao-Hui Song. GPR3 and GPR6, novel molecular targets for cannabidiol. Biochemical and Biophysical Research Communications Volume 490, Issue 1, 12 August 2017, Pages 17-21.
48 Chagas MH, Zuardi AW, Tumas V, Pena-Pereira MA, Sobreira ET, Bergamaschi MM, dos Santos AC, Teixeira AL, Hallak JE, and Crippa JA. Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial. J Psychopharmacol. 2014 Nov;28(11):1088-98.
49 Appendino G1, Gibbons S, Giana A, Pagani A, Grassi G, Stavri M, Smith E, Rahman MM. Antibacterial cannabinoids from Cannabis sativa: a structure-activity study. J Nat Prod. 2008 Aug;71(8):1427-30.
50 Ramer R, Heinemann K, Merkord J, Rohde H, Salamon A, Linnebacher M, Hinz B. COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of human lung cancer cells. Mol Cancer Ther. 2013 Jan;12(1):69-82.
51 McAllister SD, Christian RT, Horowitz MP, Garcia A, and Desprez PY. Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells. Mol Cancer Ther. 2007 Nov;6(11):2921-7.
52 Santos NA, Martins NM, Sisti FM, Fernandes LS, Ferreira RS, Queiroz RH, and Santos AC. The neuroprotection of cannabidiol against MPP+-induced toxicity in PC12 cells involves trkA receptors, upregulation of axonal and synaptic proteins, neuritogenesis, and might be relevant to Parkinson’s disease. Toxicol In Vitro. 2015 Dec 25;30(1 Pt B):231-40.
53 Sagredo O, García-Arencibia M, de Lago E, Finetti S, Decio A, and Fernández-Ruiz J. Cannabinoids and neuroprotection in basal ganglia disorders. Mol Neurobiol. 2007 Aug;36(1):82-91.
54 Sandeep Vasant More and Dong-Kug. Promising cannabinoid-based therapies for Parkinson’s disease: motor symptoms to neuroprotection. Mol Neurodegener. 2015; 10: 17.
55 Campos AC, Fogaça MV, Sonego AB, and Guimarães FS. Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol Res. 2016 Oct;112:119-127.
56 Belén G. Ramirez, Cristina Blzquez, Teresa Gomez del Pulgar, Manuel Guzman, and Marıa L. de Ceballos. Prevention of Alzheimer’s Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation. The Journal of Neuroscience, February 23, 2005 • 25(8):1904 –1913.
57 A. J. Hampson, M. Grimaldi, J. Axelrod, and D. Wink. Cannabidiol and (−)Δ9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A. 1998 Jul 7; 95(14): 8268–8273.
58 Leocani L, Nuara A, Houdayer E, Schiavetti I, Del Carro U, Amadio S, Straffi L, Rossi P, Martinelli V, Vila C, Sormani MP, and Comi G. Sativex(®) and clinical-neurophysiological measures of spasticity in progressive multiple sclerosis. J Neurol. 2015 Nov;262(11):2520-7.
59 Syed YY, McKeage K, and Scott LJ. Delta-9-tetrahydrocannabinol/cannabidiol (Sativex®): a review of its use in patients with moderate to severe spasticity due to multiple sclerosis. Drugs. 2014 Apr;74(5):563-78.
60 Novotna A, Mares J, Ratcliffe S, Novakova I, Vachova M, Zapletalova O, Gasperini C, Pozzilli C, Cefaro L, Comi G, Rossi P, Ambler Z, Stelmasiak Z, Erdmann A, Montalban X, and Klimek A, Davies P; Sativex Spasticity Study Group. A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex(®) ), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur J Neurol. 2011 Sep;18(9):1122-31.
61 Conte A, Bettolo CM, Onesti E, Frasca V, Iacovelli E, Gilio F, Giacomelli E, Gabriele M, Aragona M, Tomassini V, Pantano P, Pozzilli C, and Inghilleri M. Cannabinoid-induced effects on the nociceptive system: a neurophysiological study in patients with secondary progressive multiple sclerosis. Eur J Pain. 2009 May;13(5):472-7.
62 William Notcutt, Mario Price, Roy Miller, Samantha Newport, Cheryl Phillips, Susan Simmons, and Cathy Sansom. Initial experiences with medicinal extracts of cannabis for chronic pain: Results from 34 ‘N of 1’ studies. Anaesthesia, 59: 440–452.
63 Manini AF, Yiannoulos G, Bergamaschi MM, et al. Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans. Journal of addiction medicine. 2015;9(3):204-210.
64 Jadoon KA, Tan GD, and O’Sullivan SE. A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study. JCI Insight. 2017 Jun 15;2(12).
65 Hindocha C, Freeman TP, Schafer G, et al. Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: A randomised, double-blind, placebo-controlled study in cannabis users. European Neuropsychopharmacology. 2015;25(3):325-334.
66 Bergamaschi MM, Queiroz RHC, Chagas MHN, et al. Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Naïve Social Phobia Patients. Neuropsychopharmacology. 2011;36(6):1219-1226.
67 Das RK1, Kamboj SK, Ramadas M, Yogan K, Gupta V, Redman E, Curran HV, and Morgan CJ. Cannabidiol enhances consolidation of explicit fear extinction in humans. Psychopharmacology (Berl). 2013 Apr;226(4):781-92.
68 Crippa JA, Derenusson GN, Ferrari TB, Wichert-Ana L, Duran FL, Martin-Santos R, Simões MV, Bhattacharyya S, Fusar-Poli P, Atakan Z, Santos Filho A, Freitas-Ferrari MC, McGuire PK, Zuardi AW, Busatto GF, and Hallak JE. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011 Jan;25(1):121-30.
69 Bhattacharyya S, Morrison PD, Fusar-Poli P, et al. Opposite Effects of Δ-9-Tetrahydrocannabinol and Cannabidiol on Human Brain Function and Psychopathology. Neuropsychopharmacology. 2010;35(3):764-774.
70 Winton-Brown TT, Allen P, Bhattacharrya S, et al. Modulation of Auditory and Visual Processing by Delta-9-Tetrahydrocannabinol and Cannabidiol: an fMRI Study. Neuropsychopharmacology. 2011;36(7):1340-1348.
71 Fusar-Poli P, Allen P, Bhattacharyya S, Crippa JA, Mechelli A, Borgwardt S, Martin-Santos R, Seal ML, O’Carrol C, Atakan Z, Zuardi AW, and McGuire P. Modulation of effective connectivity during emotional processing by Delta 9-tetrahydrocannabinol and cannabidiol. Int J Neuropsychopharmacol. 2010 May;13(4):421-32.
72 Morgan CJ, Das RK, Joye A, Curran HV, and Kamboj SK. Cannabidiol reduces cigarette consumption in tobacco smokers: preliminary findings. Addict Behav. 2013 Sep;38(9):2433-6.
73 Jadoon KA, Ratcliffe SH, Barrett DA, Thomas EL, Stott C, Bell JD, O’Sullivan SE, and Tan GD. Efficacy and Safety of Cannabidiol and Tetrahydrocannabivarin on Glycemic and Lipid Parameters in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Pilot Study. Diabetes Care. 2016 Oct;39(10):1777-86.
74 Bergamaschi MM, Queiroz RH, Zuardi AW, et al. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf. 2011;6:237–249.
75 Iffland K, Grotenhermen F. 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):139-154.
76 Geffrey AL, Pollack SF, Bruno PL, et al. Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56:1246–1251.
77 Fernandes E, Fernandes M, Keeble J. The functions of TRPA1 and TRPV1: moving away from sensory nerves. British Journal of Pharmacology. 2012;166(2):510-521.
78 Jancsó-Gábor A, Szolcsányi J, Jancsó N. Stimulation and desensitization of the hypothalamic heat-sensitive structures by capsaicin in rats. J Physiol. 1970b;208:449–459.
79 Kark T, Bagi Z, Lizanecz E, Pásztor ET, Erdei N, Czikora A, et al. Tissue-specific regulation of microvascular diameter: opposite functional roles of neuronal and smooth muscle located vanilloid receptor-1. Mol Pharmacol. 2008;73:1405–1412.
80 Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sørgård M, Di Marzo V, et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature. 1999;400:452–457.
81 Ohnuki K, Haramizu S, Oki K, Watanabe T, Yazawa S, Fushiki T. Administration of capsiate, a non-pungent capsaicin analog, promotes energy metabolism and suppresses body fat accumulation in mice. Biosci Biotechnol Biochem. 2001;65:2735–2740.
82 Zhang LL, Yan Liu D, Ma LQ, Luo ZD, Cao TB, Zhong J, et al. Activation of transient receptor potential vanilloid type-1 channel prevents adipogenesis and obesity. Circ Res. 2007b;100:1063–1070.
83 R. Ramer, et al., Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1, FASEB J. 26 (4) (2012) 1535–1548.
84 R. Ramer, et al., Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1, Biochem. Pharmacol. 79 (7) (2010) 955–966.
85 Santoni G, Farfariello V, Liberati S, et al. The role of transient receptor potential vanilloid type-2 ion channels in innate and adaptive immune responses. Frontiers in Immunology. 2013;4:34.
86 Sulk M., Seeliger S., Aubert J., Schwab V. D., Cevikbas F., Rivier M., et al. (2012). . Distribution and expression of non-neuronal transient receptor potential (TRPV) ion channels in rosacea. J. Invest. Dermatol. 132 1253–1262.
87 Oláh A, Tóth BI, Borbíró I, et al. Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes. The Journal of Clinical Investigation. 2014;124(9):3713-3724.
88 Fonfria E, Murdock PR, Cusdin FS, Benham CD, Kelsell RE, McNulty S. Tissue distribution profiles of the human TRPM cation channel family. J Recept Signal Transduct Res. 2006;26(3):159-78.
89 Nelson S. Yee, Ada S. Chan, Julian D. Yee, and Rosemary K. Yee. TRPM7 and TRPM8 Ion Channels in Pancreatic Adenocarcinoma: Potential Roles as Cancer Biomarkers and Targets. Scientifica. Volume 2012 (2012), Article ID 415158, 8 pages.
90 L. De Petrocellis, et al., Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms, Br. J. Pharmacol. 168 (1) (2013) 79–102.
91 De Petrocellis L, Ligresti A, Schiano Moriello A, et al. Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms. British Journal of Pharmacology. 2013;168(1):79-102.
92 Michelle Roche and David P Finn. Brain CB2 Receptors: Implications for Neuropsychiatric Disorders. Pharmaceuticals 2010, 3, 2517-2553.
93 Alyssa S. Laun, and Zhao-Hui Song. GPR3 and GPR6, novel molecular targets for cannabidiol. Biochemical and Biophysical Research Communications. Volume 490, Issue 1, 12 August 2017, Pages 17–21.
94 Laun A. S. et al.
95 Douglas McHugh, Sherry SJ Hu, Neta Rimmerman, Ana Juknat, Zvi Vogel, J Michael Walker and Heather B Bradshaw. N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor. BMC Neuroscience201011:44.
96 Liu B, Song S, Jones PM, Persaud SJ. GPR55: from orphan to metabolic regulator? Pharmacol Ther. 2015 Jan;145:35-42.
97 Hofmann NA, Yang J, Trauger SA, Nakayama H, Huang L, Strunk D, Moses MA, Klagsbrun M, Bischoff J, Graier WF. The GPR 55 agonist, L-α-lysophosphatidylinositol, mediates ovarian carcinoma cell-induced angiogenesis. Br J Pharmacol. 2015 Aug;172(16):4107-18.
98 Andradas C, Blasco-Benito S, Castillo-Lluva S, Dillenburg-Pilla P, Diez-Alarcia R, Juanes-García A, García-Taboada E, Hernando-Llorente R, Soriano J, Hamann S, Wenners A, Alkatout I, Klapper W, Rocken C, Bauer M, Arnold N, Quintanilla M, Megías D, Vicente-Manzanares M, Urigüen, L, Gutkind JS, Guzmán M, Pérez-Gómez E, Sánchez C. Activation of the orphan receptor GPR55 by lysophosphatidylinositol promotes metastasis in triple-negative breast cancer. Oncotarget. 2016 Jul 26;7(30):47565-47575.
99 Kargl J, Andersen L, Hasenöhrl C, et al. GPR55 promotes migration and adhesion of colon cancer cells indicating a role in metastasis. Br J Pharmacol. 2015;173(1):142-54.
100 Pert CB, Snyder SH (March 1973). “Opiate receptor: demonstration in nervous tissue”. Science. 179 (4077): 1011–4.
101 Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker E. Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn Schmiedebergs Arch Pharmacol. 2006 Feb;372(5):354-61.
102 Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, 1999-2010. JAMA Intern Med. 2014;174(10):1668-1673.
103 Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther. 2011 Dec;90(6):844-51.
104 Care by Design. Cannabis in the Treatment of Age-Related Pain. Fall 2016. https://www.projectcbd.org/sites/projectcbd/files/downloads/survey_cannabis-and-pain_2016-11-02.pdf
105 Tyagi S, Gupta P, Saini AS, Kaushal C, Sharma S. The peroxisome proliferator-activated receptor: A family of nuclear receptors role in various diseases. Journal of Advanced Pharmaceutical Technology & Research. 2011;2(4):236-240.
106 Tyagi S. et al.
107 Tyagi S. et al.
108 Ramer R, Heinemann K, Merkord J, Rohde H, Salamon A, Linnebacher M, Hinz B. COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of human lung cancer cells. Mol Cancer Ther. 2013 Jan;12(1):69-82.
109 Aviello G, Romano B, Borrelli F, Capasso R, Gallo L, Piscitelli F, Di Marzo V, Izzo AA. Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer. J Mol Med (Berl). 2012 Aug;90(8):925-34.
110 Bracey MH, Hanson MA, Masuda KR, Stevens RC, Cravatt BF (November 2002). “Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling”. Science. 298 (5599): 1793–6.
111 Deutsch DG, Chin SA (September 1993). “Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist”. Biochemical Pharmacology. 46 (5): 791–6.
112 Sałaga M, Sobczak M, Fichna J (2014). “Inhibition of fatty acid amide hydrolase (FAAH) as a novel therapeutic strategy in the treatment of pain and inflammatory diseases in the gastrointestinal tract”. European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences. 52: 173–9.
113 Ghosh S, Kinsey SG, Liu QS, Hruba L, McMahon LR, Grim TW, et al. (2015). “Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice”. The Journal of Pharmacology and Experimental Therapeutics. 354 (2): 111–20.
114 Ulugöl A (2014). “The endocannabinoid system as a potential therapeutic target for pain modulation”. Balkan Medical Journal. 31 (2): 115–20.
115 Gunduz-Cinar O, Hill MN, McEwen BS, Holmes A (November 2013). “Amygdala FAAH and anandamide: mediating protection and recovery from stress”. Trends in Pharmacological Sciences. 34 (11): 637–44.
116 Berardi A, Schelling G, Campolongo P (September 2016). “The endocannabinoid system and Post Traumatic Stress Disorder (PTSD): From preclinical findings to innovative therapeutic approaches in clinical settings”. Pharmacological Research. 111: 668–78.
117 Panlilio LV, Justinova Z, Goldberg SR (2013). “Inhibition of FAAH and activation of PPAR: new approaches to the treatment of cognitive dysfunction and drug addiction”. Pharmacology & Therapeutics. 138 (1): 84–102
118 Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS (December 2012). “Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders”. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 367 (1607): 3364–78.
119 Campos A.C. et al.
120 Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Translational Psychiatry. 2012;2(3).
Chapter 3, Graphic 3
1 Tamura Y, Iwasaki Y, Narukawa M, Watanabe T. Ingestion of cinnamaldehyde, a TRPA1 agonist, reduces visceral fats in mice fed a high-fat and high-sucrose diet. J Nutr Sci Vitaminol (Tokyo). 2012;58(1):9-13.
2 Akopian, A. N., Ruparel, N. B., Jeske, N. A., Patwardhan, A., and Hargreaves, K. M. (2009) Role of ionotropic cannabinoid receptors in peripheral antinociception and antihyperalgesia Trends Pharmacol. Sci. 30, 79–84.
3 Ning Qin, Michael P. Neeper, Yi Liu, Tasha L. Hutchinson, Mary Lou Lubin and Christopher M. Flores. TRPV2 Is Activated by Cannabidiol and Mediates CGRP Release in Cultured Rat Dorsal Root Ganglion Neurons.Journal of Neuroscience 11 June 2008, 28 (24) 6231-6238.
4 De Petrocellis L, Ligresti A, Moriello AS, Allarà M, Bisogno T, Petrosino S, Stott CG, Di Marzo V. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharm. 2011;163:1479–1494.
5 Winchester WJ, Gore K, Glatt S, Petit W, Gardiner JC, Conlon K, Postlethwaite M, Saintot PP, Roberts S, Gosset JR, Matsuura T, Andrews MD, Glossop PA, Palmer MJ, Clear N, Collins S, Beaumont K, Reynolds DS. Inhibition of TRPM8 channels reduces pain in the cold pressor test in humans. Pharmacol Exp Ther. 2014 Nov;351(2):259-69.
6 De Petrocellis L, Vellani V, Schiano-Moriello A, Marini P, Magherini PC, Orlando P, et al. Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. J Pharmacol Exp Ther. 2008;325:1007–1015.
7 Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker E. Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn Schmiedebergs Arch Pharmacol. 2006 Feb;372(5):354-61.
8 Basu S, Dittel BN. Unraveling the Complexities of Cannabinoid Receptor 2 (CB2) Immune Regulation in Health and Disease. Immunologic research. 2011;51(1):26-38.
9 Bahi A, Al Mansouri S, Al Memari E, Al Ameri M, Nurulain SM, Ojha S. β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice. Physiol Behav. 2014 Aug;135:119-24.
10 Gantz I., Muraoka A., Yang Y.K., Samuelson L.C., Zimmerman E.M., Cook H., Yamada T. Cloning and chromosomal localization of a gene (GPR18) encoding a novel seven transmembrane receptor highly expressed in spleen and testis. Genomics. 1997;42:462–466.
11 Penumarti, Anusha, “Role of central cannabinoid receptor GPR18 in cardiovascular regulation” (Doctoral Dissertation., East Carolina University, January 2014).
12 Douglas McHugh, Jeremy Page, Emily Dunn, and Heather B Bradshaw. Δ9-Tetrahydrocannabinol and N-arachidonyl glycine are full agonists at GPR18 receptors and induce migration in human endometrial HEC-1B cells. British Journal of Pharmacology. Volume 165, Issue 8, April 2012, Pages 2414–2424.
13 Yu J, Deliu E, Zhang X-Q, et al. Differential Activation of Cultured Neonatal Cardiomyocytes by Plasmalemmal Versus Intracellular G Protein-coupled Receptor 55. The Journal of Biological Chemistry. 2013;288(31):22481-22492.
14 J Kargl, L Andersen, C Hasenöhrl, D Feuersinger, A Stančić, A Fauland, C Magnes, A El‐Heliebi, S Lax, 5 S Uranitsch, J Haybaeck, A Heinemann, and R Schicho. GPR55 promotes migration and adhesion of colon cancer cells indicating a role in metastasis. Br J Pharmacol. 2016 Jan; 173(1): 142–154.
15 Hofmann NA, Yang J, Trauger SA, Nakayama H, Huang L, Strunk D, Moses MA, Klagsbrun M, Bischoff J, Graier WF. The GPR 55 agonist, L-α-lysophosphatidylinositol, mediates ovarian carcinoma cell-induced angiogenesis. Br J Pharmacol. 2015 Aug;172(16):4107-18.
16 Andradas C, Blasco-Benito S, Castillo-Lluva S, Dillenburg-Pilla P, Diez-Alarcia R, Juanes-García A, García-Taboada E, Hernando-Llorente R, Soriano J, Hamann S, Wenners A, Alkatout I, Klapper W, Rocken C, Bauer M, Arnold N, Quintanilla M, Megías D, Vicente-Manzanares M, Urigüen
L, Gutkind JS, Guzmán M, Pérez-Gómez E, Sánchez C. Activation of the orphan receptor GPR55 by lysophosphatidylinositol promotes metastasis in triple-negative breast cancer. Oncotarget. 2016 Jul 26;7(30):47565-47575.
17 E Ryberg, N Larsson, S Sjögren, S Hjorth, N-O Hermansson, J Leonova, T Elebring, K Nilsson, T Drmota, P J Greasley. The orphan receptor GPR55 is a novel cannabinoid receptor. British Journal of Pharmacology (2007) 152, 1092–1101.
18 O’Sullivan SE, Tarling EJ, Bennett AJ, Kendall DA, Randall MD. Novel time-dependent vascular actions of Δ9-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor γ. Biochem Biophys Res Commun (2005) 337:824–831.
19 Krishnan A, Nair SA, Pillai MR (2007). “Biology of PPAR gamma in cancer: a critical review on existing lacunae”. Curr. Mol. Med. 7 (6): 532–40.
20 O’Sullivan SE, Tarling EJ, Bennett AJ, Kendall DA, Randall MD. Novel time-dependent vascular actions of Δ9-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor γ. Biochem Biophys Res Commun (2005) 337:824–831.
21 Bishop-Bailey D. Peroxisome proliferator-activated receptors in the cardiovascular system. British Journal of Pharmacology. 2000;129(5):823-834.
22 Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. British Journal of Pharmacology. 2007;150(5):613-623.
23 Costa B, Giagnoni G, Franke C, Trovato AE, Colleoni M. Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation. British Journal of Pharmacology. 2004;143(2):247-250.
24 Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001;134:845–852.
25 Costa B, Giagnoni G, Franke C, Trovato AE, Colleoni M. Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation. British Journal of Pharmacology. 2004;143(2):247-250.
26 Qin N, Neeper MP, Liu Y, Hutchinson TL, Lubin ML, Flores CM. TRPV2 is activated by cannabidiol and mediates CGRP release in cultured rat dorsal root ganglion neurons. J Neurosci. 2008;28:6231–6238.
27 Levine JD, Alessandri-Haber N. TRP channels: targets for the relief of pain. Biochim Biophys Acta. 2007;1772:989–1003.
28 Oláh A, Tóth BI, Borbíró I, et al. Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes. The Journal of Clinical Investigation. 2014;124(9):3713-3724.
29 Oláh A. et al.
30 De Petrocellis L, Vellani V, Schiano-Moriello A, Marini P, Magherini PC, Orlando P, et al. Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. J Pharmacol Exp Ther. 2008;325:1007–1015.
31 Ramachandran, R., Hyun, E., Zhao, L., Lapointe, T. K., Chapman, K., Hirota, C. L., Ghosh, S., McKemy, D. D., Vergnolle, N., Beck, P. L., Altier, C., and Hollenberg, M. D. TRPM8 activation attenuates inflammatory responses in mouse models of colitis Proc. Natl. Acad. Sci. U.S.A. (2013) 110, 7476– 7481.
32 De Petrocellis L, Ligresti A, Schiano Moriello A, et al. Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms. British Journal of Pharmacology. 2013;168(1):79-102.
33 Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker E. Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn Schmiedebergs Arch Pharmacol. 2006 Feb;372(5):354-61.
34 McPartland JM, Glass M, Pertwee RG. Meta-analysis of cannabinoid ligand binding affinity and receptor distribution: interspecies differences. British Journal of Pharmacology. 2007;152(5):583-593.
35 Karniol I, Carlini E. Pharmacological interaction between cannabidiol and δ9-tetrahydrocannabinol. Psychopharmacologia. 1973;33:53–70.
36 Englund A, Morrison PD, Nottage J, et al. Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol. 2013;27:19–27.
37 Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. British Journal of Pharmacology. 2007;150(5):613-623.
38 Sarah Rosenthaler, Birgit Pöhn, Caroline Kolmanz, Chi Nguyen Huu, Christopher Krewenka, Alexandra Huber, Barbara Kranner, Wolf-Dieter Rausch, Rudolf Moldzio. Differences in receptor binding affinity of several phytocannabinoids do not explain their effects on neural cell cultures. Neurotoxicology and Teratology, Volume 46 (2014), Pages 49-56.
39 Basu S, Dittel BN. Unraveling the Complexities of Cannabinoid Receptor 2 (CB2) Immune Regulation in Health and Disease. Immunologic research. 2011;51(1):26-38.
40 Bahi A, Al Mansouri S, Al Memari E, Al Ameri M, Nurulain SM, Ojha S. β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice. Physiol Behav. 2014 Aug;135:119-24.
41 Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. British Journal of Pharmacology. 2007;150(5):613-623.
42 Alyssa S. Laun, and Zhao-Hui Song. GPR3 and GPR6, novel molecular targets for cannabidiol. Biochemical and Biophysical Research Communications. Volume 490, Issue 1, 12 August 2017, Pages 17–21.
43 Laun A. S. et al.
44 Jessica Ruiz-Medina, Catherine Ledent, and Olga Valverde. GPR3 orphan receptor is involved in neuropathic pain after peripheral nerve injury and regulates morphine-induced antinociception. Neuropharmacology. Volume 61, Issues 1–2, July–August 2011, Pages 43-50.
45 Alyssa S. Laun, and Zhao-Hui Song. GPR3 and GPR6, novel molecular targets for cannabidiol. Biochemical and Biophysical Research Communications. Volume 490, Issue 1, 12 August 2017, Pages 17–21.
46 Laun A. S. et al.
47 E Ryberg, N Larsson, S Sjögren, S Hjorth, N-O Hermansson, J Leonova, T Elebring, K Nilsson, T Drmota, P J Greasley. The orphan receptor GPR55 is a novel cannabinoid receptor. British Journal of Pharmacology (2007) 152, 1092–1101.
48 Lauren S. Whytea, Erik Rybergb, Natalie A. Simsc, Susan A. Ridgea, Ken Mackied, Peter J. Greasleyb, Ruth A. Rossa, and Michael J. Rogersa. The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo. PNSA vol. 106 no. 38, 16511–16516.
49 J Kargl, L Andersen, C Hasenöhrl, D Feuersinger, A Stančić, A Fauland, C Magnes, A El‐Heliebi, S Lax, 5 S Uranitsch, J Haybaeck, A Heinemann, and R Schicho. GPR55 promotes migration and adhesion of colon cancer cells indicating a role in metastasis. Br J Pharmacol. 2016 Jan; 173(1): 142–154.
50 Hofmann NA, Yang J, Trauger SA, Nakayama H, Huang L, Strunk D, Moses MA, Klagsbrun M, Bischoff J, Graier WF. The GPR 55 agonist, L-α-lysophosphatidylinositol, mediates ovarian carcinoma cell-induced angiogenesis. Br J Pharmacol. 2015 Aug;172(16):4107-18.
51 Andradas C, Blasco-Benito S, Castillo-Lluva S, Dillenburg-Pilla P, Diez-Alarcia R, Juanes-García A, García-Taboada E, Hernando-Llorente R, Soriano J, Hamann S, Wenners A, Alkatout I, Klapper W, Rocken C, Bauer M, Arnold N, Quintanilla M, Megías D, Vicente-Manzanares M, Urigüen L, Gutkind JS, Guzmán M, Pérez-Gómez E, Sánchez C. Activation of the orphan receptor GPR55 by lysophosphatidylinositol promotes metastasis in triple-negative breast cancer. Oncotarget. 2016 Jul 26;7(30):47565-47575.
52 Leonardo BM Resstel, Rodrigo F Tavares, Sabrina FS Lisboa, Sâmia RL Joca, Fernando MA Corrêa, and Francisco S Guimarães. 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol. 2009 Jan; 156(1): 181–188.
53 Bakas T, van Nieuwenhuijzen PS, Devenish SO, McGregor IS, Arnold JC, and Chebib M. The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABAA receptor. Pharmacol Res. 2017 May;119:358-370.
54 Erica J. Carrier, John A. Auchampach, and Cecilia J. Hillard. Inhibition of an equilibrative nucleoside transporter by cannabidiol: A mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci U S A. 2006 May 16; 103(20): 7895–7900.
55 Ramer R, Heinemann K, Merkord J, Rohde H, Salamon A, Linnebacher M, Hinz B. COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of human lung cancer cells. Mol Cancer Ther. 2013 Jan;12(1):69-82.
56 Ramer R. et al.
57 Maeda T. and Kishioka S. PPAR and Pain. Int Rev Neurobiol. 2009;85:165-77.
58 Maeda T. et al.
59 Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Translational Psychiatry. 2012;2(3).
60 Leweke F.M. et al.
Chapter 3, Graphic 5 (Vitruvian Man)
1 Coutts AA, Pertwee RG. Inhibition by cannabinoid receptor agonists of acetylcholine release from the guinea-pig myenteric plexus. British Journal of Pharmacology. 1997;121(8):1557-1566.
2 Coutts A.A. et al.
3 Szabo B, Schlicker E. (2005) Effects of cannabinoids on neurotransmission. In: Pertwee R.G. (eds) Cannabinoids. Handbook of Experimental Pharmacology, Vol 168. Springer-Verlag: Heidelberg, Berlin.
4 Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker E. Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn Schmiedebergs Arch Pharmacol. 2006 Feb;372(5):354-61.
5 Szabo B, Schlicker E. (2005) Effects of cannabinoids on neurotransmission. In: Pertwee R.G. (eds) Cannabinoids. Handbook of Experimental Pharmacology, Vol 168. Springer-Verlag: Heidelberg, Berlin.
6 Schechter M, Weller A, Pittel Z, Gross M, Zimmer A, Pinhasov A. Endocannabinoid receptor deficiency affects maternal care and alters the dam’s hippocampal oxytocin receptor and brain-derived neurotrophic factor expression. J Neuroendocrinol. 2013 Oct;25(10):898-909.
7 Wei D, Lee D, Cox CD, et al. Endocannabinoid signaling mediates oxytocin-driven social reward. Proceedings of the National Academy of Sciences of the United States of America. 2015;112(45):14084-14089.
8 Szabo B, Schlicker E. (2005) Effects of cannabinoids on neurotransmission. In: Pertwee R.G. (eds) Cannabinoids. Handbook of Experimental Pharmacology, Vol 168. Springer-Verlag: Heidelberg, Berlin.
9 Cobellis G, Meccariello R, Chianese R, Chioccarelli T, Fasano S, Pierantoni R. Effects of Neuroendocrine CB1 Activity on Adult Leydig Cells. Frontiers in Endocrinology. 2016;7:47.
10 Senin LL, Al-Massadi O, Folgueira C, et al. The Gastric CB1 Receptor Modulates Ghrelin Production through the mTOR Pathway to Regulate Food Intake. Nadal A, ed. PLoS ONE. 2013;8(11):e80339.
11 Kartikkumar Navinchandra Patel, Amit Arvind Joharapurkar, Vishal Patel, Samadhan Govind Kshirsagar, Rajesh Bahekar, Brijesh Kumar Srivastava, Mukul R. Jaina. Cannabinoid receptor 1 antagonist treatment induces glucagon release and shows an additive therapeutic effect with GLP-1 agonist in diet-induced obese mice. Canadian Journal of Physiology and Pharmacology, 2014, 92(12): 975-983.
12 Lucie Jean-Gilles, Bruno Gran, Cris S. Constantinescu. Interaction between cytokines, cannabinoids and the nervous system. Immunobiology. Volume 215, Issue 8, August 2010, Pages 606-610.
13 Matthijs G Bossong, Bart NM van Berckel, Ronald Boellaard, Lineke Zuurman, Robert C Schuit, Albert D Windhorst, Joop M A van Gerven, Nick F Ramsey, Adriaan A Lammertsma & René S Kahn. Δ9-Tetrahydrocannabinol Induces Dopamine Release in the Human Striatum. Original Article | Published: 27 August 2008. Neuropsychopharmacology volume 34, pages 759–766 (2009).
14 Niederhoffer N, Hansen HH, Fernandez-Ruiz JJ, Szabo B. Effects of cannabinoids on adrenaline release from adrenal medullary cells. Br J Pharmacol. 2001 Nov;134(6):1319-27.
15 Goodwin RS, Baumann MH, Gorelick DA, et al. CB1 – Cannabinoid Receptor Antagonist Effects on Cortisol in Cannabis-Dependent Men. The American journal of drug and alcohol abuse. 2012;38(1):114-119.
16 Szabo B, Schlicker E. (2005) Effects of cannabinoids on neurotransmission. In: Pertwee R.G. (eds) Cannabinoids. Handbook of Experimental Pharmacology, Vol 168. Springer-Verlag: Heidelberg, Berlin.
17 Valeria Luc, Javier Fernandez Solari, Valeria Rettori, Andrea DeLaurentiis. The inhibitory effect of anandamide on oxytocin and vasopressin secretion from neurohypophysis is mediated by nitric oxide. Regulatory Peptides Volume 188, 10 January 2014, Pages 31-39.
18 Szabo B, Schlicker E. (2005) Effects of cannabinoids on neurotransmission. In: Pertwee R.G. (eds) Cannabinoids. Handbook of Experimental Pharmacology, Vol 168. Springer-Verlag: Heidelberg, Berlin.
19 Kim D, Kim Y, Jang H, et al Estrogen-related receptor γ controls hepatic CB1 receptor-mediated CYP2E1 expression and oxidative liver injury by alcohol Gut 2013;62:1044-1054.
20 Bosier B, Bellocchio L, Metna-Laurent M, et al. Astroglial CB1 cannabinoid receptors regulate leptin signaling in mouse brain astrocytes. Molecular Metabolism. 2013;2(4):393-404.
21 Shin H, Han JH, Yoon J, et al. Blockade of cannabinoid 1 receptor improves glucose responsiveness in pancreatic beta cells. Journal of Cellular and Molecular Medicine. 2018;22(4):2337-2345.
22 Tahamtan A, Samieipoor Y, Nayeri FS, et al. Effects of cannabinoid receptor type 2 in respiratory syncytial virus infection in human subjects and mice. Virulence. 2018;9(1):217-230.
Chapter 4: Which Chemotype Is for You?
1 Karl W. Hillig and Paul G. Mahlberg. A chemotaxonomic analysis of cannabinoid variation in Cannabis (Cannabaceae). Am. J. Bot. June 2004 vol. 91 no. 6 966-975.
2 Small E. and Beckstead H. D. Cannabinoid phenotypes in Cannabis sativa. Nature 245: 147-148. 1973.
3 Small E. and Beckstead H. D. Common cannabinoid phenotypes in 350 stocks of Cannabis. Lloydia 36: 144-165. 1973.
4 N.Escondido. The Strongest Strains on Earth. High Times. April 26, 2017. Lab testing done by Canna Safe Analytics (Murrieta CA.) Laboratory test used: High-Performance Liquid Chromatography.
5 Escondido N.
6 Escondido N.
7 Claudia Sommer, “Peripheral Neuropathies: Long-Term Opioid Therapy in Neuropathy: Benefit or Harm?” Nature Reviews Neurology 13 (2017), 516–17.
8 N. B. Finnerup, N. Attal, S. Haroutounian, et al., “Pharmacotherapy for Neuropathic Pain in Adults: Systematic Review, Meta-Analysis and Updated NeuPSIG Recommendations,” The Lancet Neurology 14:2 (2015), 162–73.
9 E. M. Hoffman, J. C. Watson, J. St. Sauver, N. P. Staff, and C. J. Klein, “Association of Long-Term Opioid Therapy with Functional Status, Adverse Out- comes, and Mortality Among Patients With Polyneuropathy,” JAMA Neurol. 74:7 (July 1, 2017), 773–79.
10 van de Donk T, Niesters M, Kowal MA, Olofsen E, Dahan A, van Velzen M. An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia. Pain. 2019;160(4):860-869.
11 J Kargl, L Andersen, C Hasenöhrl, D Feuersinger, A Stančić, A Fauland, C Magnes, A El‐Heliebi, S Lax, 5 S Uranitsch, J Haybaeck, A Heinemann, and R Schicho. GPR55 promotes migration and adhesion of colon cancer cells indicating a role in metastasis. Br J Pharmacol. 2016 Jan; 173(1): 142–154.
12 Andradas C, Blasco-Benito S, Castillo-Lluva S, Dillenburg-Pilla P, Diez-Alarcia R, Juanes-García A, García-Taboada E, Hernando-Llorente 12 Hofmann NA, Yang J, Trauger SA, Nakayama H, Huang L, Strunk D, Moses MA, Klagsbrun M, Bischoff J, Graier WF. The GPR 55 agonist, L-α-lysophosphatidylinositol, mediates ovarian carcinoma cell-induced angiogenesis. Br J Pharmacol. 2015 Aug;172(16):4107-18.
13 Andradas C, Blasco-Benito S, Castillo-Lluva S, Dillenburg-Pilla P, Diez-Alarcia R, Juanes-García A, García-Taboada E, Hernando-Llorente R, Soriano J, Hamann S, Wenners A, Alkatout I, Klapper W, Rocken C, Bauer M, Arnold N, Quintanilla M, Megías D, Vicente-Manzanares M, Urigüen L, Gutkind JS, Guzmán M, Pérez-Gómez E, Sánchez C. Activation of the orphan receptor GPR55 by lysophosphatidylinositol promotes metastasis in triple-negative breast cancer. Oncotarget. 2016 Jul 26;7(30):47565-47575.
14 GW Pharmaceuticals. Prescriber Information. https://www.gwpharm.com/healthcare-professionals/sativex
15 Bayer and GW Pharmaceutical Ltd. Sativex Oromucosal Spray, Patient Information Leaflet. Last changes May 20, 2015.
16 N. Escondido. High Times. The Strongest Strains on Earth. May 2017. Page 80.
17 N. Escondido.
18 Patent. Hayley’s Comet CA 2737447 A1. Filling Date Apr 27, 2011.
19 Hornby P, Sharma M. Standardized cannabis in multiple sclerosis: a case report. Cases J. 2010;3:7. Published 2010 Jan 6. doi:10.1186/1757-1626-3-7
20 N. Escondido. The Strongest Strains on Earth. High Times. June 1, 2016. Lab testing done by Canna Safe Analytics (Murrieta CA.) Laboratory test used: High-Performance Liquid Chromatography.
21 Escondido N.
22 Escondido N.
23 GW Pharmaceuticals. Epidiolex. https://www.gwpharm.com/healthcare-professionals/epidiolex
24 Ibid.
25 Orrin Devinsky, Joseph Sullivan, Daniel Friedman, Elizabeth Thiele, Eric Marsh, Linda Laux, Julie Hedlund, Nicole Tilton, Judith Bluvstein and Maria Cilio. Efficacy and Safety of Epidiolex (Cannabidiol) in Children and Young Adults with Treatment-Resistant Epilepsy: Initial Data From an Expanded Access Program. American Epilepsy Society. Annual Meeting Abstracts: Views. (Abst. 3.303), 2014.
26 Mateus Machado Bergamaschi, Regina Helena Costa Queiroz, José Alexandre S. Crippa, and Antonio Waldo Zuardi. Safety and Side Effects of Cannabidiol, a Cannabis sativa Constituent. Current Drug Safety, 2011, Vol. 6, No. 4. (13 pages).
27 Geffrey AL, Pollack SF, Bruno PL, et al. Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56:1246–1251.
28 Srivastava MD, Srivastava BI, Brouhard B.. D9-Tetrahydrocannabinol and cannabidiol alter cytokine production by human immune cells. Immunopharmacology 1998; 40(3): 179-85.
29 Gallily, R., Yekhtin, Z. and Hanuš, L.O. (2015) Overcoming the Bell‐Shaped Dose‐Response of Can‐ nabidiol by Using Cannabis Extract Enriched in Cannabidiol. Pharmacology & Pharmacy, 6, 75‐85.
30 Fournier G., Richez-Dumanois C., Duvezin J., Mathieu J.-P. and Paris M. Identification of a new chemotype in Cannabis sativa: cannabigerol-dominant plants, biogenetic and agronomic prospects. Plant. Med. 1987. 53: 277–280.
31 Mandolino G. and Carboni A. 2004. Potential of marker assisted selection in hemp genetic improvement. Euphytica 140: 107–120.
Chapter 5: The CannaKeys Process
1 Stephanie M. Todd, Cilla Zhou, David J. Clarke, Tariq W. Chohan, Dilara Bahceci, Jonathon C. Arnold. Interactions between cannabidiol and Δ9-THC following acute and repeated dosing: Rebound hyperactivity, sensorimotor gating and epigenetic and neuroadaptive changes in the mesolimbic pathway. European Neuropsychopharmacology, Volume null, Issue null, Page null.
2 Nahas, G. G. (1975) Marijuana: toxicity and tolerance. In Medical Aspects of Drug Abuse (ed. R. W. Richter), pp. 16-36. Baltimore, MD: Harper & Row.
3 Ochs M, Nyengaard JR, Jung A, Knudsen L, Voigt M, Wahlers T, Richter J, Gundersen HJ. The number of alveoli in the human lung. Am J Respir Crit Care Med. 2004 Jan 1;169(1):120-4.
4 Perez-Reyes M. Marijuana smoking: factors that influence the bioavailability of tetrahydrocannabinol. NIDA Res. Monogr 99. 1990;42-62.
5 Hollister LE, Gillespie HK (1975). “Action of delta-9-tetrahydrocannabinol. An approach to the active metabolite hypothesis”. Clin. Pharmacol. Ther. 18 (6): 714–9.
6 Gaffal E, Cron M, Glodde N, Tüting T. Anti-inflammatory activity of topical THC in DNFB-mediated mouse allergic contact dermatitis independent of CB1 and CB2 receptors. Allergy. 2013 Aug;68(8):994-1000.
7 Soliman E, Henderson KL, Danell AS, Van Dross R. Arachidonoyl-ethanolamide activates endoplasmic reticulum stress-apoptosis in tumorigenic keratinocytes: Role of cyclooxygenase-2 and novel J-series prostamides. Mol Carcinog. 2015 Jan 3.
8 Valiveti S, Hammell DC, Earles DC, Stinchcomb AL. In vitro/in vivo correlation studies for transdermal delta 8-THC development.J Pharm Sci. 2004 May; 93(5):1154-64.
9 Cone EJ, Huestis MA. Relating blood concentrations of tetrahydrocannabinol and metabolites to pharmacologic effects and time of marijuana usage. Ther Drug Monit. 1993 Dec;15(6):527-32.
10 Gallily, R. , Yekhtin, Z. and Hanuš, L. Overcoming the Bell-Shaped Dose-Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol. Pharmacology & Pharmacy. (2015); 6, 75-85.
11 Prasanthi D, Lakshmi PK. Terpenes: Effect of lipophilicity in enhancing transdermal delivery of alfuzosin hydrochloride. J Adv Pharm Technol Res. 2012;3(4):216–223.
12 Rock EM1, Kopstick RL, Limebeer CL, and Parker LA. Tetrahydrocannabinolic acid reduces nausea-induced conditioned gaping in rats and vomiting in Suncus murinus. Br J Pharmacol. 2013 Oct;170(3):641-8.
13 Moldzio R1, Pacher T, Krewenka C, Kranner B, Novak J, Duvigneau JC, and Rausch WD. Effects of cannabinoids Δ(9)-tetrahydrocannabinol, Δ(9)-tetrahydrocannabinolic acid and cannabidiol in MPP+ affected murine mesencephalic cultures. Phytomedicine. 2012 Jun 15;19(8-9):819-24.
14 Lucia Renee Ruhaak, Jenny Felth, Pernilla Christina Karlsson, Joseph James Rafter, Robert Verpoorte, and Lars Bohlin. Evaluation of the Cyclooxygenase Inhibiting Effects of Six Major Cannabinoids Isolated from Cannabis sativa. Biol. Pharm. Bull. 34(5) 774—778 (2011).
15 D Bolognini, EM Rock, NL Cluny, MG Cascio, CL Limebeer, M Duncan, CG Stott, FA Javid, LA Parker, and RG Pertwee. Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation. Br J Pharmacol. 2013 Mar; 168(6): 1456–1470.
16 Rock EM, Limebeer CL, Navaratnam R, Sticht MA, Bonner N, Engeland K, Downey R, Morris H, Jackson M, and Parker LA. A comparison of cannabidiolic acid with other treatments for anticipatory nausea using a rat model of contextually elicited conditioned gaping. Psychopharmacology (Berl). 2014 Aug;231(16):3207-15.
17 Rock EM and Parker LA. Effect of low doses of cannabidiolic acid and ondansetron on LiCl-induced conditioned gaping (a model of nausea-induced behaviour) in rats. Br J Pharmacol. 2013 Jun;169(3):685-92.
18 Takeda S, Okajima S, Miyoshi H, Yoshida K, Okamoto Y, Okada T, Amamoto T, Watanabe K, Omiecinski CJ, Aramaki H. Cannabidiolic acid, a major cannabinoid in fiber-type cannabis, is an inhibitor of MDA-MB-231 breast cancer cell migration. Toxicol Lett. 2012 Nov 15;214(3):314-9.
19 Adam Orens, Miles Light, Jacob Rowberry, Jeremy Matsen, and Brian Lewandowski. Prepared for the Colorado Department of Revenue. Marijuana Equivalency in Portion and Dosage. An assessment of physical and pharmacokinetic relationships in marijuana production and consumption in Colorado. August 10, 2015.
20 Takeda S1, Okajima S, Miyoshi H, Yoshida K, Okamoto Y, Okada T, Amamoto T, Watanabe K, Omiecinski CJ, Aramaki H. Cannabidiolic acid, a major cannabinoid in fiber-type cannabis, is an inhibitor of MDA-MB-231 breast cancer cell migration. Toxicol Lett. 2012 Nov 15;214(3):314-9.
21 Wang Mei, Wang Yan-Hong, Avula Bharathi, Radwan Mohamed M., Wanas Amira S., van Antwerp John, Parcher Jon F., ElSohly Mahmoud A., and Khan Ikhlas A.. Decarboxylation Study of Acidic Cannabinoids: A Novel Approach Using Ultra-High-Performance Supercritical Fluid Chromatography/Photodiode Array-Mass Spectrometry. Cannabis and Cannabinoid Research. Volume: 1 Issue 1: December 1, 2016.
22 Lanz C, Mattsson J, Soydaner U, Brenneisen R (2016) Medicinal Cannabis: In Vitro Validation of Vaporizers for the Smoke-Free Inhalation of Cannabis. PLoS ONE 11(1): e0147286.
23 M. Kahn and Scott Churchill. Dosing Cannabis Accurately using a Vaporizer: White Paper. Enhancing Dose Uniformity and Therapeutic Product Efficiency. MCR Labs (2014). Framingham, MA. https://www.scribd.com/document/234082060/White-Paper-Vape-Ex
24 Barth Wilsey, MD, Thomas D. Marcotte, PhD, Reena Deutsch, PhD, Ben Gouaux, Staci Sakai, and Haylee Donaghe. Low Dose Vaporized Cannabis Significantly Improves Neuropathic Pain. J Pain. 2013 Feb; 14(2): 136–148.
25 Bilkei-Gorzo A, Albayram O, Draffehn A, Michel K, Piyanova A, Oppenheimer H, Dvir-Ginzberg M, Rácz I, Ulas T, Imbeault S, Bab I, Schultze JL, Zimmer A. A chronic low dose of ∆9-tetrahydrocannabinol (THC) restores cognitive function in old mice. Nat Med. 2017 May 8. 9 pages. 10.1038/nm.4311.
26 Bilkei-Gorzo A. et al.
27 Adams TB, Taylor SV. Safety evaluation of essential oils: a constituent-based approach. In: Baser KHC, Buchbauer G, editors. Handbook of Essential Oils: Science, Technology, and Applications. Boca Raton, FL: CRC Press; 2010. pp. 185–208, specifically page 192.
28 Dickerson, Sally S., MA, Margaret E. Kemeny, PhD, Najib Aziz, MD, Kevin H. Kim, PhD, and John L. Fahey, MD. 2004. “Immunological Effects of Induced Shame and Guilt.” Psychosomatic Medicine 66:124–31.
29 Miller, T. Q., Smith, T. W., Turner, C. W., Guijarro, M. L., & Hallet, A. J. (1996). A meta-analytic review of research on hostility and physical health. Psychological Bulletin, 119, 322-348.
30 LeShan, Lawrence, PhD. Cancer as a Turning Point: A Handbook for People with Cancer, eir Families, and Health Professionals (A Plume Book, 1989).
31 Mann, S.J., and Delon, M. 1995 (Sep-Oct). “Improved hypertension control after disclosure of decades-old trauma.” Psychosomatic Medicine 57(5):501–05.
32 Everett L. Worthington Jr. & Michael Scherer (2004): Forgiveness is an emotion- focused coping strategy that can reduce health risks and promote health resilience: theory, review, and hypotheses, Psychology & Health, 19:3, 385-405.
33 Thoresen, C.E., Harris, A.H.S., and Luskin, F. 2000. Forgiveness: Theory, Research, and Practice (New York: Guilford Press), pp. 254–80.
Appendix: The Science Behind the Top 10
Cancer
1 Szymon Hryhorowicz, Michal Walczak, Oliwia Zakerska-Banaszak, Ryszard Słomski, and Marzena Skrzypczak-Zielińska. Pharmacogenetics of Cannabinoids. Eur J Drug Metab Pharmacokinet. 2018; 43(1): 1–12.
2 Cristina Sánchez, Ismael Galve-Roperh, Cecile Canova, Philippe Brachet and Manuel Guzmán. Δ9-Tetrahydrocannabinol induces apoptosis in C6 glioma cells. FEBS Letters. Volume 436, Issue 1, 25 September 1998, Pages 6-10.
3 Sánchez C, de Ceballos ML, Gomez del Pulgar T, Rueda D, Corbacho C, Velasco G, Galve-Roperh I, Huffman JW, Ramón y Cajal S, and Guzmán M. Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res. 2001 Aug 1;61(15):5784-9.
4 Massi, Paola, Angelo Vaccani, Stefania Ceruti, Arianna Colombo, Maria P. Abbracchio, and Daniela Parolaro. 2004 (March). “Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines.” JPET 308(3):838–45.
5 Massi, P., Vaccani, A., Bianchessi, S., Costa, B., Macchi, P., and Parolaro, D. 2006 (Sep). “The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells.” Cell Mol Life Sci. 63(17):2057–66.
6 Blázquez, Cristina, Luis González-Feria, Luis Álvarez, Amador Haro, M. Llanos Casanova, and Manuel Guzmán. 2004 (Aug 15). “Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas.” Cancer Res. 64:5617.
7 Vaccani A, Massi P, Colombo A, Rubino T, Parolaro D. Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism. British Journal of Pharmacology. 2005;144(8):1032-1036
8 Massi P, Vaccani A, Bianchessi S, Costa B, Macchi P, and Parolaro D. The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells. Cell Mol Life Sci. 2006 Sep;63(17):2057-66.
9 Massi P, Solinas M, Cinquina V, Parolaro D. Cannabidiol as potential anticancer drug. British Journal of Clinical Pharmacology. 2013;75(2):303-312.
10 Guzman, M., Duarte, M.J., Blazquez, C., Ravina, J., Rosa, M.C., Galve- Roperh, I., Sanchez, C., Velasco, G., and Gonzalez-Feria, L. 2006. “A pilot clinical study of Delta(9)-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme.” Br J Cancer 95(2):197–203.
11 Galanti G, Fisher T, Kventsel I, Shoham J, Gallily R, Mechoulam R, Lavie G, Amariglio N, Rechavi G, and Toren A. Delta 9-tetrahydrocannabinol inhibits cell cycle progression by downregulation of E2F1 in human glioblastoma multiforme cells. Acta Oncol. 2008;47(6):1062-70.
12 Cristina Blazquez, Arkaitz Carracedo, Maria Salazar, Mar Lorente, Ainara Egia, Luis Gonzalez-Feria, Amador Haro, Guillermo Velasco, and Manuel Guzman. Down-regulation of tissue inhibitor of metalloproteinases-1 in gliomas: a new marker of cannabinoid antitumoral activity? Neuropharmacology 54 (2008) 235-243.
13 Hernández-Tiedra S, Fabriàs G, Dávila D, et al. Dihydroceramide accumulation mediates cytotoxic autophagy of cancer cells via autolysosome destabilization. Autophagy. 2016;12(11):2213-2229.
14 Marcu JP, Christian RT, Lau D, et al. Cannabidiol enhances the inhibitory effects of Δ9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival. Molecular cancer therapeutics. 2010;9(1):180-189.
15 Moteki H, Hibasami H, Yamada Y, Katsuzaki H, Imai K, Komiya T. Specific induction of apoptosis by 1,8-cineole in two human leukemia cell lines, but not a in human stomach cancer cell line. Oncol Rep. 2002 Jul-Aug;9(4):757-60.
16 Miller, J. A., Lang, J. E., Ley, M., Nagle, R., Hsu, C.-H., Thompson, P. A., Chow, H.-H. S. Human breast tissue disposition and bioactivity of limonene in women with early stage breast cancer. Cancer Prevention Research (Philadelphia, Pa.), (2013). 6(6), 577–584.
17 Loizzo MR, Tundis R, Menichini F, Saab AM, Statti GA, and Menichini F. Antiproliferative effects of essential oils and their major constituents in human renal adenocarcinoma and amelanotic melanoma cells. Cell Prolif. 2008 Dec;41(6):1002-12.
18 Ravizza R, Gariboldi MB, Molteni R, Monti E. Linalool, a plant-derived monoterpene alcohol, reverses doxorubicin resistance in human breast adenocarcinoma cells. Oncol Rep. 2008 Sep;20(3):625-30.
19 Chiang LC, Chiang W, Chang MY, Ng LT, and Lin CC. Antileukemic activity of selected natural products in Taiwan. Am J Chin Med. 2003;31(1):37-46.
20 Weiqiang Chena, Ying Liua, Ming Lia, Jianwen Maoa, Lirong Zhanga, Rongbo Huanga, Xiaobao Jina, and Lianbao Yeb. Anti-tumor effect of α-pinene on human hepatoma cell lines through inducing G2/M cell cycle arrest. Journal of Pharmacological Sciences
Volume 127, Issue 3, March 2015, Pages 332–338
21 Saadia Bashir Hassan, Hala Gali-Muhtasib, Hanna Göransson and Rolf Larsson. Alpha Terpineol: A Potential Anticancer Agent which Acts through Suppressing NF-κB Signalling. Anticancer Research June 2010 vol. 30 no. 6 1911-1919.
22 Lampronti I, Saab AM, Gambari R : Antiproliferative activity of essential oils derived from plants belonging to the Magnoliophyta division. Int J Oncol 29(4): 989-995, 2006.
23 Dahham S. S., Tabana Y. M., Iqbal M. A., Ahamed M. B., Ezzat M. O., Majid A. S., et al. 2015. The Anticancer, antioxidant and antimicrobial properties of the Sesquiterpene β‐Caryophyllene from the essential Oil of Aquilaria crassna. Molecules 20:11808–11829.
24 Jung J. I., Kim E. J., Kwon G. T., Jung Y. J., Park T., Kim Y., et al. 2015. β‐Caryophyllene potently inhibits solid tumor growth and lymph node metastasis of B16F10 melanoma cells in high‐fat diet‐induced obese C57BL/6N mice. Carcinogenesis 36:1028–1039.
25 Loizzo MR, Tundis R, Menichini F, Saab AM, Statti GA, and Menichini F. Antiproliferative effects of essential oils and their major constituents in human renal adenocarcinoma and amelanotic melanoma cells. Cell Prolif. 2008 Dec;41(6):1002-12.
26 Chen TC, Fonseca COD, Schönthal AH. Preclinical development and clinical use of perillyl alcohol for chemoprevention and cancer therapy. American Journal of Cancer Research. 2015;5(5):1580-1593.
27 da Fonseca CO, Schwartsmann G, Fischer J, Nagel J, Futuro D, Quirico-Santos T, and Gattass CR. Preliminary results from a phase I/II study of perillyl alcohol intranasal administration in adults with recurrent malignant gliomas. Surg Neurol. 2008 Sep;70(3):259-66; discussion 266-7.
28 da Fonseca CO, Simão M, Lins IR, Caetano RO, Futuro D, and Quirico-Santos T. Efficacy of monoterpene perillyl alcohol upon survival rate of patients with recurrent glioblastoma. J Cancer Res Clin Oncol. 2011 Feb;137(2):287-93.
29 Sofía Torres, Mar Lorente, Fátima Rodríguez-Fornés, Sonia Hernández-Tiedra, María Salazar, Elena García-Taboada, Juan Barcia, Manuel Guzmán and Guillermo Velasco. A Combined Preclinical Therapy of Cannabinoids and Temozolomide against Glioma. MCT. January 2011. Volume 10, Issue 1.
30 Nabissi M, Morelli MB, Santoni M, and Santoni G. Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents. Carcinogenesis. 2013 Jan;34(1):48-57.
31 Ivanov VN, Wu J, and Hei TK. Regulation of human glioblastoma cell death by combined treatment of cannabidiol, γ-radiation and small molecule inhibitors of cell signaling pathways. Oncotarget. 2017 May 27;8(43):74068-74095.
Heart Disease
1 Ashton, J.C., and Smith, P.F. 2007 (Jul). “Cannabinoids and cardiovascular disease: The outlook for clinical treatments.” Curr Vasc Pharmacol. 5(3):175–85.
2 Shmist, Y.A., Goncharov, I., Eichler, M., Shneyvays, V., Isaac, A., Vogel, Z., and Shainberg, A. 2006 (Feb). “Delta-9-tetrahydrocannabinol protects cardiac cells from hypoxia via CB2 receptor activation and nitric oxide production.” Mol Cell Biochem 283(1-2):75–83.
3 Hayakawa, K., Mishima, K., Abe, K., Hasebe, N., Takamatsu, F., Yasuda, H., Ikeda, T., Inui, K., Egashira, N., Iwasaki, K., and Fujiwara, M. 2004 (Oct 25). “Cannabidiol prevents infarction via the non-CB1 cannabinoid receptor mechanism.” Neuroreport 15(15):2381–85.
4 Jicha CJ, Lofwall MR, Nuzzo PA, Babalonis S, Elayi SC, and Walsh SL. Safety of oral dronabinol during opioid withdrawal in humans. Drug Alcohol Depend. 2015 Dec 1;157:179-83.
5 Karniol IG, Shirakawa I, Takahashi RN, Knobel E, and Musty RE. Effects of delta9-tetrahydrocannabinol and cannabinol in man. Pharmacology. 1975;13(6):502-12.
6 Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf. 2011;6:237–49.
7 Resstel, L.B., Tavares, R.F., Lisboa, S.F., Joca, S.R, Corrêa, F.M., and Guim- arães, F.S. 2009 (Jan). “5-HT receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats.” Br J Pharmacol. 156(1):181–88.
8 Jadoon KA, Tan GD, O’Sullivan SE. A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study. JCI Insight. 2017;2(12):e93760. doi:10.1172/jci.insight.93760.
9 Hsueh WA, Bruemmer D. Peroxisome proliferator-activated receptor gamma: implications for cardiovascular disease. Hypertension. 2004;43:297–305.
10 Bishop-Bailey D. Peroxisome proliferator-activated receptors in the cardiovascular system. Br J Pharmacol. 2000;129:823–34.
11 Gomes FV, Resstel LB, Guimaraes FS. The anxiolytic-like effects of cannabidiol injected into the bed nucleus of the stria terminalis are mediated by 5-HT1A receptors. Psychopharmacology. 2011;213:465–73.
12 Kühn H, Heydeck D, Hugou I, and Gniwotta C (1997) In vivo action of 15-lipoxygenase in early stages of human atherogenesis. J Clin Invest 99:888–893.
13 Shuso Takeda, Noriyuki Usami, Ikuo Yamamoto, and Kazuhito Watanabe. Cannabidiol-2 ,6 -Dimethyl Ether, a Cannabidiol Derivative, Is a Highly Potent and Selective 15-Lipoxygenase Inhibitor. Drug Metabolism and Disposition. Vol. 37, No. 8. 1733–1737, 2009.
14 Mirko Lanuti, Emanuela Talamonti, Mauro Maccarrone, and Valerio Chiurchiù. Activation of GPR55 Receptors Exacerbates oxLDL-Induced Lipid Accumulation and Inflammatory Responses, while Reducing Cholesterol Efflux from Human Macrophages. PLoS One. 2015; 10(5): e0126839.
15 Zhao Y, Yuan Z, Liu Y, Xue J, Tian Y, Liu W, Zhang W, Shen Y, Xu W, Liang X, Chen T. Activation of cannabinoid CB2 receptor ameliorates atherosclerosis associated with suppression of adhesion molecules. J Cardiovasc Pharmacol. 2010 Mar;55(3):292-8.
16 Gertsch J, Leonti M, Raduner S, et al. Beta-caryophyllene is a dietary cannabinoid. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(26):9099-9104.
17 Walsh SK, Hepburn CY, Kane KA, Wainwright CL. Acute administration of cannabidiol in vivo suppresses ischaemia-induced cardiac arrhythmias and reduces infarct size when given at reperfusion. British Journal of Pharmacology. 2010;160(5):1234-1242.
18 Walsh et al.
19 Durst R, Danenberg H, Gallily R, Mechoulam R, Meir K, Grad E, Beeri R, Pugatsch T, Tarsish E, Lotan C. Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury. Am J Physiol Heart Circ Physiol. 2007;293:H3602–7.
20 Walsh SK, Hepburn CY, Kane KA, Wainwright CL. Acute administration of cannabidiol in vivo suppresses ischaemia-induced cardiac arrhythmias and reduces infarct size when given at reperfusion. British Journal of Pharmacology. 2010;160(5):1234-1242
21 Walsh et al.
22 Subrata Kumar Biswas, “Does the Interdependence between Oxidative Stress and Inflammation Explain the Antioxidant Paradox?,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 5698931, 9 pages, 2016.
23 Booz GW. Cannabidiol as an Emergent Therapeutic Strategy for Lessening the Impact of Inflammation on Oxidative Stress. Free radical biology & medicine. 2011;51(5):1054-1061.
24 Yamreudeewong W1, Wong HK, Brausch LM, Pulley KR. Probable interaction between warfarin and marijuana smoking. Ann Pharmacother. 2009 Jul;43(7):1347-53.
Pain
1 Petzke F, Enax-Krumova EK, and Häuser W. Efficacy, tolerability and safety of cannabinoids for chronic neuropathic pain: A systematic review of randomized controlled studies. Schmerz. 2016 Feb;30(1):62-88.
2 Agarwal N, Pacher P, Tegeder I, et al. Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nature neuroscience. 2007;10(7):870-879.
3 Walker JM, Hohmann AG. Cannabinoid mechanisms of pain suppression. Handb Exp Pharmacol. 2005;168:509–554.
4 Agarwal N, Pacher P, Tegeder I, et al. Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nature neuroscience. 2007;10(7):870-879.
5 Notcutt W, Price M, Miller A, et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 ‘N of 1’ studies. Anaesthesia. 2004;59:440–52.
6 Dyson A, Peacock M, Chen A, Courade JP, Yaqoob M, Groarke A, Brain C, Loong Y, and Fox A. Antihyperalgesic properties of the cannabinoid CT-3 in chronic neuropathic and inflammatory pain states in the rat. Pain. 2005 Jul;116(1-2):129-37.
7 Karst M, Salim K, Burstein S, et al. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA. 2003;290:1757–62.
8 Eisenberg E, Ogintz M, and Almog S. The pharmacokinetics, efficacy, safety, and ease of use of a novel portable metered-dose cannabis inhaler in patients with chronic neuropathic pain: a phase 1a study. J Pain Palliat Care Pharmacother. 2014 Sep;28(3):216-25.
9 Ware, Mark A. Boulanger, and Aline et al. Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS). The Journal of Pain, (2015) Volume 16, Issue 12, 1233 - 1242.
10 Haroutounian S1, Ratz Y, Ginosar Y, Furmanov K, Saifi F, Meidan R, and Davidson E. The Effect of Medicinal Cannabis on Pain and Quality-of-Life Outcomes in Chronic Pain: A Prospective Open-label Study. Clin J Pain. 2016 Dec;32(12):1036-1043.
11 Bellnier T, Brown GW, Ortega TR. Preliminary evaluation of the efficacy, safety, and costs associated with the treatment of chronic pain with medical cannabis. Ment Health Clin. 2018;8(3):110–115. Published 2018 Apr 26.
12 van de Donk T, Niesters M, Kowal MA, Olofsen E, Dahan A, van Velzen M. An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia. Pain. 2019;160(4):860–869. doi:10.1097/j.pain.0000000000001464
13 Sumariwalla P. F., Gallily R., Tchilibon S., Fride E., Mechoulam R., Feldmann M. A novel synthetic, nonpsychoactive cannabinoid acid (HU-320) with antiinflammatory properties in murine collagen-induced arthritis. Arthritis Rheum. 2004;50(3):985–998.
14 Costa B., Trovato A. E., Comelli F., Giagnoni G., Colleoni M. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. Eur. J. Pharmacol. 2007;556(1–3):75–83.
15 Adam Orens, Miles Light, Jacob Rowberry, Jeremy Matsen, and Brian Lewandowski. Prepared for the Colorado Department of Revenue. Marijuana Equivalency in Portion and Dosage. An assessment of physical and pharmacokinetic relationships in marijuana production and consumption in Colorado. August 10, 2015.
Diabetes
1 Jadoon KA, Ratcliffe SH, Barrett DA, Thomas EL, Stott C, Bell JD, O'Sullivan SE, Tan GD. Efficacy and Safety of Cannabidiol and Tetrahydrocannabivarin on Glycemic and Lipid Parameters in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Pilot Study. Diabetes Care. 2016 Oct;39(10):1777-86.
2 Weiss, L., Zeira, M., Reich, S., Slavin, S., Raz, I., Mechoulam, R., and Gallily, R. 2008 (Jan). “Cannabidiol arrests onset of autoimmune diabetes in NOD mice.” Neuropharmacology 54(1):244-49. Also Weiss, L., Zeira, M., Reich, S., Har-Noy, M., Mechoulam, R., Slavin, S., and Gallily, R. 2006 (Mar). “Cannabidiol lowers incidence of diabetes in non-obese diabetic mice.” Autoimmunity 39(2):143–51.
3 Zhang, F., Challapalli, S.C., and Smith, P.J. 2009 (Aug). “Cannabinoid CB(1) receptor activation stimulates neurite outgrowth and inhibits capsaicin-induced Ca(2+) influx in an in vitro model of diabetic neuropathy.” Neuropharmacology 57(2):88–96.
4 El-Remessy, Azza B., Mohamed Al-Shabrawey, Yousuf Khalifa, Nai-Tse Tsai, Ruth B. Caldwell, and Gregory I. Liou. 2006. “Neuroprotective and blood- retinal barrier-preserving effects of cannabidiol in experimental diabetes.” American Journal of Pathology 168:235–44.
5 Li, X., Kaminski, N.E., and Fischer, L.J. 2001 (Apr). “Examination of the immunosuppressive effect of delta9-tetrahydrocannabinol in streptozotocin-induced autoimmune diabetes.” Int Immunopharmacol. 1(4):699–712.
6 Wargent ET, Zaibi MS, Silvestri C, et al. The cannabinoid Δ(9)-tetrahydrocannabivarin (THCV) ameliorates insulin sensitivity in two mouse models of obesity. Nutr Diabetes. 2013;3(5):e68. Published 2013 May 27. doi:10.1038/nutd.2013.9
7 Khalid A. Jadoon, Stuart H. Ratcliffe, David A. Barrett, E. Louise Thomas, Colin Stott, Jimmy D. Bell, Saoirse E. O’Sullivan and Garry D. Tan. Efficacy and Safety of Cannabidiol and Tetrahydrocannabivarin on Glycemic and Lipid Parameters in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Pilot Study. Diabetes Care 2016 Oct; 39(10): 1777-1786.
8 Thomas A, Stevenson LA, Wease KN, et al. Evidence that the plant cannabinoid Delta9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist. Br J Pharmacol. 2005;146(7):917–926.
9 Suijun W, Zhen Y, Ying G, Yanfang W. A role for trans-caryophyllene in the moderation of insulin secretion. Biochem Biophys Res Commun. 2014 Feb 21;444(4):451-4.
Anxiety
1 Kessler, Ronald C., PhD, Wai Tat Chiu, AM, Olga Demler, MA, MS, and Ellen E. Walters, MS. 2005 (Jun). “Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replica- tion.” Arch Gen Psychiatry 62(6):617–27.
2 Gunduz-Cinar O, Hill MN, McEwen BS, Holmes A. Amygdala FAAH and anandamide: mediating protection and recovery from stress. Trends Pharmacol Sci. 2013;34:637–644.
3 Dincheva I, Drysdale AT, Hartley CA, et al. FAAH genetic variation enhances fronto-amygdala function in mouse and human. Nat Commun. 2015;6:6395. Published 2015 Mar 3. doi:10.1038/ncomms7395
4 Hariri AR, Gorka A, Hyde LW, et al. Divergent effects of genetic variation in endocannabinoid signaling on human threat- and reward-related brain function. Biol Psychiatry. 2008;66(1):9-16.
5 McPartland JM, Glass M, Pertwee RG. Meta-analysis of cannabinoid ligand binding affinity and receptor distribution: interspecies differences. British Journal of Pharmacology. 2007;152(5):583-593.
6 Bhattacharyya S, Morrison PD, Fusar-Poli P, et al. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology. 2009;35(3):764-74.
7 Das RK, Kamboj SK, Ramadas M, Yogan K, Gupta V, Redman E, Curran HV, Morgan CJ. Cannabidiol enhances consolidation of explicit fear extinction in humans. Psychopharmacology (Berl). 2013 Apr;226(4):781-92.
8 Crippa JA, Derenusson GN, Ferrari TB, Wichert-Ana L, Duran FL, Martin-Santos R, Simões MV, Bhattacharyya S, Fusar-Poli P, Atakan Z, Santos Filho A, Freitas-Ferrari MC, McGuire PK, Zuardi AW, Busatto GF, Hallak JE. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011 Jan;25(1):121-30.
9 McPartland JM, Giuffrida A, King J, Skinner E, Scotter J, Musty RE. Cannabimimetic effects of osteopathic manipulative treatment. J Am Osteopath Assoc. 2005 Jun;105(6):283-91.
10 Linares IM, Zuardi AW, Pereira LC, Queiroz RH, Mechoulam R, Guimarães FS, Crippa JA. Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test. Rev Bras Psiquiatr. 2018 Oct 11.
11 Bergamaschi MM, Queiroz RH, Chagas MH, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology. 2011;36(6):1219-26.
12 Gulluni N, Re T, Loiacono I, et al. Cannabis Essential Oil: A Preliminary Study for the Evaluation of the Brain Effects. Evid Based Complement Alternat Med. 2018;2018:1709182.
13 Gulluni N. et al.
14 Gulluni N. et al.
15 Bahi A, Al Mansouri S, Al Memari E, Al Ameri M, Nurulain SM, Ojha S. β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice. Physiol Behav. 2014 Aug;135:119-24.
16 Harada H, Kashiwadani H, Kanmura Y and Kuwaki T (2018) Linalool Odor-Induced Anxiolytic Effects in Mice. Front. Behav. Neurosci. 12:241.
17 Buchbauer G, Jirovetz L, Jager W, Plank C, Dietrich H. Fragrance compounds and essential oils with sedative effects upon inhalation. J Pharm Sci. 1993;82:660–664.
18 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.
19 Binet L, Binet P, Miocque M, Roux M, Bernier A. Recherches sur les proprietes pharmcodynamiques (action sedative et action spasmolytique) de quelques alcools terpeniques aliphatiques. Ann Pharm Fr. 1972;30:611–616.
20 Ito K and Ito M. The sedative effect of inhaled terpinolene in mice and its structure-activity relationships. Journal of Natural Medicines. Jan 2013, 67(4):833-837.
21 d'Alessio PA, Bisson JF, Béné MC. Anti-stress effects of d-limonene and its metabolite perillyl alcohol. Rejuvenation Res. 2014 Apr;17(2):145-9.
22 de Almeida AA1, Costa JP, de Carvalho RB, de Sousa DP, de Freitas RM. Evaluation of acute toxicity of a natural compound (+)-limonene epoxide and its anxiolytic-like action. Brain Res. 2012 Apr 11;1448:56-62
23 Park HM1, Lee JH, Yaoyao J, Jun HJ, Lee SJ. Limonene, a natural cyclic terpene, is an agonistic ligand for adenosine A(2A) receptors. Biochem Biophys Res Commun. 2011 Jan 7;404(1):345-8.
24 The Human Genome Project. http://drnelson.uthsc.edu/human.P450.table.html
Multiple Sclerosis
1 Elovaara, Irina, MD, PhD; Maritta Ukkonen, MD; Minna Leppakynnas, MD; Terho Lehtimaki, MD, PhD; Mari Luomala, MSc; Jukka Peltola, MD; and Prasun Dastidar, MD. 2000. “Adhesion molecules in multiple sclerosis—Relation to subtypes of disease and methylprednisolone therapy.” Arch Neurol. 57:546–51.
Insomnia
1 Fujimori M, Himwich HE. Delta 9-tetrahydrocannabinol and the sleep-wakefulness cycle in rabbits. Physiol Behav. 1973 Sep;11(3):291-5.
2 Feinberg I, Jones R, Walker JM, Cavness C, March J. Effects of high dosage delta-9-tetrahydrocannabinol on sleep patterns in man. Clin Pharmacol Ther. 1975 Apr;17(4):458-66.
3 Adams PM, Barratt ES. Effect of chronic marijuana administration of stages of primate sleep-wakefulness. Biol Psychiatry. 1975 Jun;10(3):315-22.
4 Feinberg I, Jones R, Walker J, Cavness C, Floyd T. Effects of marijuana extract and tetrahydrocannabinol on electroencephalographic sleep patterns. Clin Pharmacol Ther. 1976 Jun;19(6):782-94.
5 Jaime M. Monti. Hypnoticlike effects of cannabidiol in the rat. Psychopharmacology, January 1977, Volume 55, Issue 3, pp 263–265.
6 Carlini EA, Cunha JM. Hypnotic and antiepileptic effects of cannabidiol. J Clin Pharmacol. 1981 Aug-Sep;21(8-9 Suppl):417S-427S.
7 Murillo-Rodríguez E1, Sánchez-Alavez M, Navarro L, Martínez-González D, Drucker-Colín R, Prospéro-García O. Anandamide modulates sleep and memory in rats. Brain Res. 1998 Nov 23;812(1-2):270-4.
8 Anthony N. Nicholson, MD, PhD, Claire Turner, BSc, Barbara M. Stone, PhD, and Philip J. Robson, MD. Effect of D-9-Tetrahydrocannabinol and Cannabidiol on Nocturnal Sleep and Early-Morning Behavior in Young Adults. Journal of Clinical Psychopharmacology. Volume 24, Number 3, June 2004.
9 Wendy Swift, Peter Gates, and Paul Dillon. Survey of Australians using cannabis for medical purposes. Harm Reduct J. 2005; 2:18.
10 Eric Murillo-Rodríguez, Andrea Sarro-Ramírez, Daniel Sánchez, Stephanie Mijangos-Moreno, Alma Tejeda-Padrón, Alwin Poot-Aké, Khalil Guzmán, Elda Pacheco-Pantoja, and Oscar Arias-Carrión. Potential Effects of Cannabidiol as a Wake-Promoting Agent. Curr Neuropharmacol. 2014 May; 12(3): 269–272.
11 Shannon S, Opila-Lehman J. Effectiveness of Cannabidiol Oil for Pediatric Anxiety and Insomnia as Part of Posttraumatic Stress Disorder: A Case Report. Perm J. 2016 Fall;20(4):108-111.
12 David A. Gorelick MD, PhD, Robert S. Goodwin DO, PhD, Eugene Schwilke PhD, Jennifer R. Schroeder PhD, David M. Schwope PhD, Deanna L. Kelly PharmD, Catherine Ortemann-Renon PharmD, PhD, Denis Bonnet MD, Marilyn A. Huestis PhD. Around-the-clock oral THC effects on sleep in male chronic daily cannabis smokers. The American Journal on Addiction. Volume 22, Issue 5, September–October 2013 Pages 510–514.
13 Rolando Tringale, MD and Claudia Jensen, MD. Cannabis and Insomnia. O’Shaughnessy’s • Autumn 2011. Pg. 31-32.
14 Crippa JA, Zuardi AW, Martín-Santos R, Bhattacharyya S, Atakan Z, McGuire P, Fusar-Poli P. Cannabis and anxiety: a critical review of the evidence. Hum Psychopharmacol. 2009 Oct;24(7):515-23.
15 Noriyuki Usami, Takeshi Okuda, Hisatoshi Yoshida, Toshiyuki Kimura, Kazuhito Watanabe, Hidetoshi Yoshimura, and Ikuo Yamamoto. Synthesis and Pharmacological Evaluation in Mice of Halogenated Cannabidiol Derivatives. Chem. Pharm. Bull. 47(11) 1641—1645 (1999).
16 Takahashi RN, Karniol IG. Pharmacologic interaction between cannabinol and delta9-tetrahydrocannabinol. Psychopharmacologia. 1975;41(3):277-84.
17 McPartland JM, Giuffrida A, King J, Skinner E, Scotter J, and Musty RE. Cannabimimetic effects of osteopathic manipulative treatment. J Am Osteopath Assoc. 2005 Jun;105(6):283-91.
18 E. Heyman, F. X. Gamelin, M. Goekint, F. Piscitelli, B. Roelands, E. Leclair, V. Di Marzo, and R. Meeusen, “Intense Exercise Increases Circulating Endocannabinoid and BDNF Levels in Humans—Possible Implications for Reward and Depression,” Psychoneuroendocrinology 37:6 (June 2012), 844–51; D.
19 A. Raichlen, A. D. Foster, G. L. Gerdeman, A. Seillier, and A. Giu Rida, “Wired to Run: Exercise-Induced Endocannabinoid Signaling in Humans and Cursorial Mammals with Implications for the ‘Runner’s High.’” J. Exp. Biol. 215 (April 15, 2012), 1331–36.
20 McPartland JM, Guy GW, Di Marzo V. Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System. Romanovsky AA, ed. PLoS ONE. 2014;9(3):e89566.
21 Adam Orens, Miles Light, Jacob Rowberry, Jeremy Matsen, and Brian Lewandowski. Prepared for the Colorado Department of Revenue. Marijuana Equivalency in Portion and Dosage. An assessment of physical and pharmacokinetic relationships in marijuana production and consumption in Colorado. August 10, 2015.
Colitis
1 Ford, A.C., Talley, N.J., Spiegel, B.M., Foxx-Orenstein, A.E., Schiller, L., Quigley, E.M., and Moayyedi, P. “Effect of fibre, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome: Systematic review and meta-analysis.” BMJ 337:a2313.
2 Dejesus E, Rodwick BM, Bowers D, Cohen CJ, Pearce D. Use of Dronabinol Improves Appetite and Reverses Weight Loss in HIV/AIDS-Infected Patients. J Int Assoc Physicians AIDS Care (Chic) 2007;6:95–100.
3 Schicho R, Storr M. IBD: Patients with IBD find symptom relief in the Cannabis field. Nat Rev Gastroenterol Hepatol. 2014;11:142–3.
4 Gerich ME, Isfort RW, Brimhall B, Siegel CA. Medical Marijuana for Digestive Disorders: High Time to Prescribe? Am J Gastroenterol. 2015 Feb;110(2):208-14.
5 Lu, Dai, Kiran Vemuri, V., Duclos, Richard I., Jr., and Makriyannis, Alexan- dros. 2006 (Jul). “The cannabinergic system as a target for anti-inflammatory therapies.” Current Topics in Medicinal Chemistry 6(13):1401–26(26). Bentham Science Publishers.
6 Storr, M.A., Keenan, C.M., Emmerdinger, D., Zhang, H., Yüce, B., Sibaev, A., Massa, F., Buckley, N.E., Lutz, B., Göke, B., Brand, S., Patel, K.D., and Sharkey, K.A. 2008 (Aug). “Targeting endocannabinoid degradation protects against experimental colitis in mice: involvement of CB(1) and CB(2) recep- tors.” J Mol Med. (Berl). 86(8):925–36.
7 Capasso, R., Borrelli, F., Aviello, G., Romano, B., Scalisi, C., Capasso, F., and Izzo, A. 2008 (Jul). “Cannabidiol, extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice.” Br J Pharmacol. 154(5):1001–08.
8 Ravikoff Allegretti J, Courtwright A, Lucci M, Korzenik JR, Levine J. Marijuana use patterns among patients with inflammatory bowel disease. Inflamm Bowel Dis. 2013;19:2809–14.
9 Storr M, Devlin S, Kaplan GG, Panaccione R, Andrews CN. Cannabis use provides symptom relief in patients with inflammatory bowel disease but is associated with worse disease prognosis in patients with Crohn's disease. Inflamm Bowel Dis. 2014;20:472–80.
10 Lal S, Prasad N, Ryan M, Tangri S, Silverberg MS, Gordon A, Steinhart H. Cannabis use amongst patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2011;23:891–6.
11 Izzo, A.A., and Sharkey, K.A. 2010 (Apr). “Cannabinoids and the gut: New developments and emerging concepts.” Pharmacol Ther. 126(1):21–38.
12 Naftali T, Bar-Lev Schleider L, Dotan I, Lansky EP, Sklerovsky Benjaminov F, Konikoff FM. Cannabis induces a clinical response in patients with Crohn's disease: a prospective placebo-controlled study. Clin Gastroenterol Hepatol. 2013 Oct;11(10):1276-1280.
13 Pagano E, Capasso R, Piscitelli F, et al. An Orally Active Cannabis Extract with High Content in Cannabidiol attenuates Chemically-induced Intestinal Inflammation and Hypermotility in the Mouse. Front Pharmacol. 2016;7:341.
14 Leinwand KL, Gerich ME, Hoffenberg EJ, Collins CB. Manipulation of the Endocannabinoid System in Colitis: A Comprehensive Review. Inflamm Bowel Dis. 2017;23(2):192-199.
15 Bento AF, Marcon R, Dutra RC, Claudino RF, Cola M, Leite DF, Calixto JB. β-Caryophyllene inhibits dextran sulfate sodium-induced colitis in mice through CB2 receptor activation and PPARγ pathway. Am J Pathol. 2011 Mar;178(3):1153-66.
16 Sabulal B., Dan M., Kurup R., Pradeep N. S., Valsamma R. K., and George V.. 2006. Caryophyllene‐rich rhizome oil of Zingiber nimmonii from South India: chemical characterization and antimicrobial activity. Phytochemistry 67:2469–2473.
17 Sun J. D-Limonene: safety and clinical applications. Altern Med Rev. 2007 Sep;12(3):259-64.
18 Bonamin F, Moraes TM, Dos Santos RC, Kushima H, Faria FM, Silva MA, Junior IV, Nogueira L, Bauab TM, Souza Brito AR, da Rocha LR, Hiruma-Lima CA. The effect of a minor constituent of essential oil from Citrus aurantium: The role of β-myrcene in preventing peptic ulcer disease. Chem Biol Interact. 2014;212:11-9.
19 Cluny NL, Keenan CM, Reimer RA, Le Foll B, Sharkey KA. Prevention of Diet-Induced Obesity Effects on Body Weight and Gut Microbiota in Mice Treated Chronically with Δ9-Tetrahydrocannabinol. PLoS One. 2015;10(12):e0144270. Published 2015 Dec 3.
Cough
1 Morice A, Kardos P. Comprehensive evidence-based review on European antitussives. BMJ Open Respiratory Research. 2016;3(1):e000137.
2 P.V. Dicpinigaitis, A.H. Morice, S.S. Birring, L. McGarvey, J.A. Smith, B.J. Canning and C.P. Page. Antitussive Drugs. Pharmacological Reviews April 1, 2014, 66 (2) 468-512.
3 Fashner J, Ericson K, and Werner S. Treatment of the common cold in children and adults. Am Fam Physician. 2012 Jul 15;86(2):153-9.
4 Gordon, R., Gordon, R.J., So a, D. 1976 (Feb). “Antitussive activity of some naturally occurring cannabinoids in anesthetized cats.” Eur J Pharmacol. 35(2):309–13.
5 Patel HJ, Birrell MA, Crispino N, et al. Inhibition of guinea-pig and human sensory nerve activity and the cough reflex in guinea-pigs by cannabinoid (CB2) receptor activation. British Journal of Pharmacology. 2003;140(2):261-268.
6 United States Patent Application 20060013777. Kind Code A1. Piomelli; Daniele. January 19, 2006. Assignee: The Regents of the University of California. Filed September 12, 2005.
7 Jeanette M. Tetrault, MD; Kristina Crothers, MD; Brent A. Moore, PhD; Reena Mehra, MD, MS; John Concato, MD, MS, MPH; David A. Fiellin, MD. 2007. “Effects of marijuana smoking on pulmonary function and respiratory complications. A systematic review.” Arch Intern Med. 167(3):221–28.
8 Tan, W.C., Lo, C., Jong, A., Xing, L., Fitzgerald, M.J., Vollmer, W.M., Buist, S.A., and Sin, D.D. 2009 (Apr 14). “Marijuana and chronic obstructive lung disease: A population-based study.” CMAJ 180(8):814–20.
9 Makwana R, Venkatasamy R, Spina D, and Page C. The effect of phytocannabinoids on airway hyper-responsiveness, airway inflammation, and cough. J Pharmacol Exp Ther. 2015 Apr;353(1):169-80.
10 Shang VC, Kendall DA, and Roberts RE. Δ9-Tetrahydrocannabinol reverses TNFα-induced increase in airway epithelial cell permeability through CB2 receptors. Biochem Pharmacol. 2016 Nov 15;120:63-71.
11 Wortley MA, Adcock JJ, Dubuis ED, Maher SA, Bonvini SJ, Delescluse I, Kinloch R, McMurray G, Perros-Huguet C, Papakosta M, Birrell MA, and Belvisi MG. Targeting fatty acid amide hydrolase as a therapeutic strategy for antitussive therapy. Eur Respir J. 2017 Sep 20;50(3).
12 Kehrl, W.; Sonnemann, U.; Dethlefsen, U. "Therapy for Acute Nonpurulent Rhinosinusitis with Cineole: Results of a Double-Blind, Randomized, Placebo-Controlled Trial". The Laryngoscope. (2004). 114 (4): 738–742.
13 Juergens, U. R.; Dethlefsen, U.; Steinkamp, G.; Gillissen, A.; Repges, R.; Vetter, H. (March 2003). "Anti-Inflammatory Activity of 1.8-Cineol (Eucalyptol) in Bronchial Asthma: A Double-Blind Placebo-Controlled Trial" (pdf). Respiratory Medicine. 97 (3): 250–256.
14 Juergens, U. R.; Stöber, M.; Vetter, H. (1998). "Inhibition of Cytokine Production and Arachidonic Acid Metabolism by Eucalyptol (1.8-Cineole) in Human Blood Monocytes in vitro". European Journal of Medical Research. 3 (11): 508–510.
15 Falk AA, Hagberg MT, Lof AE, Wigaeus-Hjelm EM, Wang ZP. Uptake, distribution and elimination of alpha-pinene in man after exposure by inhalation. Scand J Work Environ Health. 1990;16:372–378.
16 Satoshi Yamaori, Yasuka Okamoto, Ikuo Yamamoto and Kazuhito Watanabe. Cannabidiol, a Major Phytocannabinoid, As a Potent Atypical Inhibitor for CYP2D6. Drug Metabolism and Disposition November 2011, 39 (11) 2049-2056.
Acne
1 Kupczyk P, Reich A, Szepietowski JC. Cannabinoid system in the skin - a possible target for future therapies in dermatology. Exp Dermatol. 2009;18(8):669–679.
2 Bíró T, et al. The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities. Trends Pharmacol Sci. 2009;30(8):411–420.
3 Tóth BI, et al. Endocannabinoids modulate human epidermal keratinocyte proliferation and survival via the sequential engagement of cannabinoid receptor-1 and transient receptor potential vanilloid-1. J Invest Dermatol. 2011;131(5):1095–1104.
4 Telek A, et al. Inhibition of human hair follicle growth by endo- and exocannabinoids. FASEB J. 2007;21(13):3534–3541.
5 Dobrosi N, et al. Endocannabinoids enhance lipid synthesis and apoptosis of human sebocytes via cannabinoid receptor-2-mediated signaling. FASEB J. 2008;22(10):3685–3695.
6 Karsak M, et al. Attenuation of allergic contact dermatitis through the endocannabinoid system. Science. 2007;316(5830):1494–1497.
7 Oláh A, Tóth BI, Borbíró I, et al. Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes. The Journal of Clinical Investigation. 2014;124(9):3713-3724.
8 Dobrosi N, Tóth BI, Nagy G, Dózsa A, Géczy T, Nagy L, Zouboulis CC, Paus R, Kovács L, Bíró T. Endocannabinoids enhance lipid synthesis and apoptosis of human sebocytes via cannabinoid receptor-2-mediated signaling. FASEB J. 2008 Oct;22(10):3685-95.
9 Oláh A, Tóth BI, Borbíró I, et al. Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes. The Journal of Clinical Investigation. 2014;124(9):3713-3724.
10 Baz K, Emin Erdal M, Yazici AC, Söylemez F, Güvenç U, Taşdelen B, Ikizoğlu G. Association between tumor necrosis factor-alpha gene promoter polymorphism at position -308 and acne in Turkish patients. Arch Dermatol Res. 2008 Aug;300(7):371-6.
11 Oláh A, Tóth BI, Borbíró I, et al. Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes. The Journal of Clinical Investigation. 2014;124(9):3713-3724.
12 Oláh A. et al.
13 Bíró, Tamás, Balázs I. Tóth, György Haskó, Ralf Paus, and Pál Pacher. 2009 (Aug). “The endocannabinoid system of the skin in health and disease: Novel perspectives and therapeutic opportunities.” Trends Pharmacol Sci. 30(8):411–20.
14 Jae Yoon Jung, Hyuck Hoon Kwon, Jong Soo Hong, Ji Young Yoon, Mi Sun Park, Mi Young Jang, and Dae Hun Suh. Effect of Dietary Supplementation with Omega-3 Fatty Acid and Gamma-linolenic Acid on Acne Vulgaris: A Randomised, Double-blind, Controlled Trial. DOI: 10.2340/00015555-1802
15 Gertsch J, Leonti M, Raduner S, et al. Beta-caryophyllene is a dietary cannabinoid. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(26):9099-9104.
16 Park HM1, Lee JH, Yaoyao J, Jun HJ, Lee SJ. Limonene, a natural cyclic terpene, is an agonistic ligand for adenosine A(2A) receptors. Biochem Biophys Res Commun. 2011 Jan 7;404(1):345-8.
17 d'Alessio PA, Ostan R, Bisson JF, Schulzke JD, Ursini MV, Béné MC. Oral administration of d-limonene controls inflammation in rat colitis and displays anti-inflammatory properties as diet supplementation in humans. Life Sci. 2013 Jul 10;92(24-26):1151-6.
18 d'Alessio PA, Bisson JF, Béné MC. Anti-stress effects of d-limonene and its metabolite perillyl alcohol. Rejuvenation Res. 2014 Apr;17(2):145-9.
19 Komori T, Fujiwara R, Tanida M, Nomura J, Yokoyama MM. Effects of citrus fragrance on immune function and depressive states. Neuroimmunomodulation. 1995;2:174–180.
20 de Almeida AA1, Costa JP, de Carvalho RB, de Sousa DP, de Freitas RM. Evaluation of acute toxicity of a natural compound (+)-limonene epoxide and its anxiolytic-like action. Brain Res. 2012 Apr 11;1448:56-62
21 Kim SS, Baik JS, Oh TH, Yoon WJ, Lee NH, Hyun CG. Biological activities of Korean Citrus obovoides and Citrus natsudaidai essential oils against acne-inducing bacteria. Biosci Biotechnol Biochem. 2008;72:2507–2513.
22 Williams AC, Barry BW : Terpenes and the lipid-protein-partitioning theory of skin penetration enhancement. Pharm Res 8(1): 17-24,
23 Raduner S, Majewska A, Chen JZ, Xie XQ, Hamon J, Faller B, et al. Alkylamides from Echinacea are a new class of cannabinomimetics. Cannabinoid type-2 receptor-dependent and –independent immunomodulatory effects. J Biol Chem. 2006;281:S14192–S1S206.
24 Chicca A, Raduner S, Pellati F, Strompen T, Altmann KH, Schoop R, et al. Synergistic immunomopharmacological effects of N-alkylamides in Echinacea purpurea herbal extracts. Int Immunopharmacol. 2009;9:S850–S858.
Forms of Cannabis
1 Raber JC, Elzinga S, and Kaplan C. Understanding dabs: contamination concerns of cannabis concentrates and cannabinoid transfer during the act of dabbing. J Toxicol Sci. 2015 Dec;40(6):797-803.
2 Varlet V, Concha-Lozano N, Berthet A, et al. Drug vaping applied to cannabis: Is “Cannavaping” a therapeutic alternative to marijuana? Scientific Reports. 2016;6:25599.
3 Jiries Meehan-Atrash, Wentai Luo, and Robert M. Strongin. Toxicant Formation in Dabbing: The Terpene Story. ACS Omega, 2017, 2 (9), pp 6112–6117.
4 Loflin M, and Earleywine M. A new method of cannabis ingestion: the dangers of dabs? Addict Behav. 2014 Oct;39(10):1430-3.
5 Berkeley Municipal Code. Medical Cannabis Dispensaries and Collectives. Article II. 12.27.070. Product safety and quality.
6 Perez-Reyes M. Marijuana smoking: factors that influence the bioavailability of tetrahydrocannabinol. NIDA Res. Monogr 99. 1990;42-62.
7 Adam Orens, Miles Light, Jacob Rowberry, Jeremy Matsen, and Brian Lewandowski. Prepared for the Colorado Department of Revenue. Marijuana Equivalency in Portion and Dosage. An assessment of physical and pharmacokinetic relationships in marijuana production and consumption in Colorado. August 10, 2015.
Terpenes and Your Health
1 Ben-Shabat S, Fride E, Sheskin T, Tamiri T, Rhee MH, Vogel Z, Bisogno T, De Petrocellis L, Di Marzo V, and Mechoulam R. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol. 1998 Jul 17;353(1):23-31.
2 C. Bushdid, M. O. Magnasco, L. B. Vosshall, A. Keller. Humans Can Discriminate More than 1 Trillion Olfactory Stimuli. Science. March 21, 2014. Vol. 343. Pages 1370-1372.
3 Jasper H. B. de Groot, Monique A. M. Smeets, Annemarie Kaldewaij, Maarten J. A. Duijndam, Maarten J. A. Duijndam, Gün R. Semin. Chemosignals Communicate Human Emotions. Psychological Science. Volume: 23 issue: 11, page(s): 1417-1424.
4 Busse, Daniela et al. A Synthetic Sandalwood Odorant Induces Wound-Healing Processes in Human Keratinocytes via the Olfactory Receptor OR2AT4. Journal of Investigative Dermatology, Volume 134 , Issue 11 , 2823 - 2832.
5 Marc Spehr, Günter Gisselmann, Alexandra Poplawski, Jeffrey A. Riffell, Christian H. Wetzel, Richard K. Zimmer, and Hanns Hatt. Identification of a Testicular Odorant Receptor Mediating Human Sperm Chemotaxis. Science 28 Mar 2003: Vol. 299, Issue 5615, pp. 2054-2058.
6 Sayorwan W, Siripornpanich V, Piriyapunyaporn T, Hongratanaworakit T, Kotchabhakdi N, Ruangrungsi N. The effects of lavender oil inhalation on emotional states, autonomic nervous system, and brain electrical activity. J Med Assoc Thai. 2012 Apr;95(4):598-606.
7 Tanida M, Shen J, Niijima A, Yamatodani A, Oishi K, Ishida N, Nagai K. Effects of olfactory stimulations with scents of grapefruit and lavender oils on renal sympathetic nerve and blood pressure in Clock mutant mice. Auton Neurosci. 2008 May 30;139(1-2):1-8.
8 Nagai K, Niijima A, Horii Y, Shen J, Tanida M. Olfactory stimulatory with grapefruit and lavender oils change autonomic nerve activity and physiological function. Auton Neurosci. 2014 Oct;185:29-35.
9 Tanida M, Niijima A, Shen J, Nakamura T, Nagai K. Olfactory stimulation with scent of lavender oil affects autonomic neurotransmission and blood pressure in rats. Neurosci Lett. 2006 May 1;398(1-2):155-60.
10 Redd WH, Manne SL, Peters B, Jacobsen PB, Schmidt H. Fragrance administration to reduce anxiety during MR imaging. J Magn Reson Imaging. 1994 Jul-Aug;4(4):623-6.
11 Diego MA, Jones NA, Field T, Hernandez-Reif M, Schanberg S, Kuhn C, McAdam V, Galamaga R, Galamaga M. Aromatherapy positively affects mood, EEG patterns of alertness and math computations. Int J Neurosci. 1998 Dec;96(3-4):217-24.
12 Cornwell PA, Barry BW. Sesquiterpene components of volatile oils as skin penetration enhancers for the hydrophilic permeant 5-fluorouracil. J Pharm Pharmacol. 1994;46:261–269
13 Komiya M, Takeuchi T, Harada E. Lemon oil vapor causes an anti-stress effect via modulating the 5-HT and DA activities in mice. Behav Brain Res. 2006;172:240–249.
14 Komori T, Fujiwara R, Tanida M, Nomura J, Yokoyama MM. Effects of citrus fragrance on immune function and depressive states. Neuroimmunomodulation. 1995;2:174–180.
15 Perry NS, Houghton PJ, Theobald A, Jenner P, Perry EK. In-vitro inhibition of human erythrocyte acetylcholinesterase by salvia lavandulaefolia essential oil and constituent terpenes. J Pharm Pharmacol. 2000;52:895–902.
16 Re L, Barocci S, Sonnino S, Mencarelli A, Vivani C, Paolucci G, et al. Linalool modifies the nicotinic receptor-ion channel kinetics at the mouse neuromuscular junction. Pharmacol Res. 2000;42:177–182.
17 Gertsch J, Leonti M, Raduner S, et al. Beta-caryophyllene is a dietary cannabinoid. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(26):9099-9104.
18 Bob B. Buchanan, Wilhelm Gruissem, and Russell L. Jones. Biochemistry and Molecular Biology of Plants. John Wiley and Sons Ltd. 1st Edition, 2015. (page 1133).
19 Vito Mediavilla and Simon Steinemann. Essential oil of Cannabis sativa L. strains. Swiss Federal Research Station for Agroecology and Agriculture, Reckenholzstrasse 191, 8046 Zurich, Switzerland.
20 Rudolf Brenneisen. Chemistry and Analysis of Phytocannabinoids and Other Cannabis Constituents. Chapter 2 from the series Forensic Science and Medicine: Marijuana and the Cannabinoids. Edited by: M. A. ElSohly © Humana Press Inc., Totowa, New Jersey. 2007.
21 Adams TB, Taylor SV. Safety evaluation of essential oils: a constituent-based approach. In: Baser KHC, Buchbauer G, editors. Handbook of Essential Oils: Science, Technology, and Applications. Boca Raton, FL: CRC Press; 2010. pp. 185–208, specifically page 192.
22 Ross SA, ElSohly MA. The volatile oil composition of fresh and air-dried buds of Cannabis sativa. J Nat Prod. 1996;59:49–51.
Borneol
1 Liu SL1. Therapeutic effects of borneol-walnut oil in the treatment of purulent otitis media. Zhong Xi Yi Jie He Za Zhi. 1990 Feb;10(2):93-5, 69.
2 Wang S, Zhang D, Hu J, Jia Q, Xu W, Su D, Song H, Xu Z, Cui J, Zhou M, Yang J, and Xiao J. A clinical and mechanistic study of topical borneol-induced analgesia. EMBO Mol Med. 2017 Apr 10. pii: e201607300.
Camphene
1 Moqrich, A.; Hwang, Sun Wook; Earley, Taryn J.; Petrus, Matt J.; Murray, Amber N.; Spencer, Kathryn S. R.; Andahazy, Mary; Story, Gina M.; Patapoutian, Ardem (2005). "Impaired Thermosensation in Mice Lacking TRPV3, a Heat and Camphor Sensor in the Skin". Science. 307 (5714): 1468–72.
2 Lucindo Quintans-Júnior, José C. F. Moreira, Matheus A. B. Pasquali, Soheyla M. S. Rabie, André S. Pires, Rafael Schröder, Thallita K. Rabelo, João P. A. Santos, Pollyana S. S. Lima, Sócrates C. H. Cavalcanti, Adriano A. S. Araújo, Jullyana S. S. Quintans, and Daniel P. Gelain. Antinociceptive Activity and Redox Profile of the Monoterpenes (+)-Camphene, p-Cymene, and Geranyl Acetate in Experimental Models. ISRN Toxicology. Volume 2013 (2013), Article ID 459530, 11 pages.
3 Ioanna Vallianou, Nikolaos Peroulis, Panayotis Pantazis, and Margarita Hadzopoulou-Cladaras. Camphene, a Plant-Derived Monoterpene, Reduces Plasma Cholesterol and Triglycerides in Hyperlipidemic Rats Independently of HMG-CoA Reductase Activity. PLoS ONE 6(11): e20516.
4 Rowa Pharmaceuticals Ltd. Newtown, Ireland. Rowachol Capsules. A medical product authorized by the European Economic Area (EEA).
Eucalyptol
1 Kehrl, W.; Sonnemann, U.; Dethlefsen, U. "Therapy for Acute Nonpurulent Rhinosinusitis with Cineole: Results of a Double-Blind, Randomized, Placebo-Controlled Trial". The Laryngoscope. (2004). 114 (4): 738–742.
2 Juergens, U. R.; Dethlefsen, U.; Steinkamp, G.; Gillissen, A.; Repges, R.; Vetter, H. (March 2003). "Anti-Inflammatory Activity of 1.8-Cineol (Eucalyptol) in Bronchial Asthma: A Double-Blind Placebo-Controlled Trial" (pdf). Respiratory Medicine. 97 (3): 250–256.
3 Juergens, U. R.; Stöber, M.; Vetter, H. (1998). "Inhibition of Cytokine Production and Arachidonic Acid Metabolism by Eucalyptol (1.8-Cineole) in Human Blood Monocytes in vitro". European Journal of Medical Research. 3 (11): 508–510.
4 Santos, F. A.; Rao, V. S. (2000). "Antiinflammatory and Antinociceptive Effects of 1,8-Cineole, a Terpenoid Oxide Present in many Plant Essential Oils". Phytotherapy Research. 14 (4): 240–244.
5 Moteki H, Hibasami H, Yamada Y, Katsuzaki H, Imai K, Komiya T. Specific induction of apoptosis by 1,8-cineole in two human leukemia cell lines, but not a in human stomach cancer cell line. Oncol Rep. 2002 Jul-Aug;9(4):757-60.
6 Mark Moss and Lorraine Oliver. Plasma 1,8-cineole correlates with cognitive performance following exposure to rosemary essential oil aroma. Ther Adv Psychopharmacol. 2012 Jun; 2(3): 103–113.
7 Winai Sayorwan, Nijsiri Ruangrungsi, Teerut Piriyapunyporn, Tapanee Hongratanaworakit, Naiphinich Kotchabhakdi, and Vorasith Siripornpanich. Sci Pharm. 2013 Apr-Jun; 81(2): 531–542.
Geraniol
1 Sathya Prasad and Murali Muralidhara. Neuroprotective effect of geraniol and curcumin in an acrylamide model of neurotoxicity in Drosophila melanogaster: Relevance to neuropathy. J Insect Physiol. 2014 Jan;60:7-16.
2 Yadollah Azarmi, Mohammdi A., and Hossein Babaei. Role of endothelium on relaxant effect of geraniol in isolated rat aorta. Pharmaceutical Sciences, 2009, Vol.14, No.4, Page311- 319.
Limonene
1 Falk-Filipsson A, Lof A, Hagberg M, Hjelm EW, Wang Z. d-limonene exposure to humans by inhalation: uptake, distribution, elimination, and effects on the pulmonary function. J Toxicol Environ Health. 1993;38:77–88.
2 Miller, J. A., Lang, J. E., Ley, M., Nagle, R., Hsu, C.-H., Thompson, P. A., Chow, H.-H. S. Human breast tissue disposition and bioactivity of limonene in women with early stage breast cancer. Cancer Prevention Research (Philadelphia, Pa.), (2013). 6(6), 577–584.
3 Wilson MJ, Lindgren BR, Sinha AA. The effect of dietary supplementation with limonene or myo-inositol on the induction of neoplasia and matrix metalloproteinase and plasminogen activator activities in accessory sex organs of male Lobund-Wistar rats. Exp Mol Pathol. 2008;85:83–9.
4 Falk-Filipsson A, Lof A, Hagberg M, Hjelm EW, Wang Z. d-limonene exposure to humans by inhalation: uptake, distribution, elimination, and effects on the pulmonary function. J Toxicol Environ Health. 1993;38:77–88.
5 Sun J. D-Limonene: safety and clinical applications. Altern Med Rev. 2007 Sep;12(3):259-64.
6 d'Alessio PA, Ostan R, Bisson JF, Schulzke JD, Ursini MV, Béné MC. Oral administration of d-limonene controls inflammation in rat colitis and displays anti-inflammatory properties as diet supplementation in humans. Life Sci. 2013 Jul 10;92(24-26):1151-6.
7 Jesudoss Victor Antony Santiago, Jayaraman Jayachitra, Madhavan Shenbagam, Namasivayam Nalini. d-limonene attenuates blood pressure and improves the lipid and antioxidant status in high fat diet and L-NAME treated rats. J. Pharm. Sci. & Res. Vol.2 (11), 2010,752-758.
8 Jesudoss V. A. S. et al.
9 Komori T, Fujiwara R, Tanida M, Nomura J, Yokoyama MM. Effects of citrus fragrance on immune function and depressive states. Neuroimmunomodulation. 1995;2:174–180.
10 d'Alessio PA, Bisson JF, Béné MC. Anti-stress effects of d-limonene and its metabolite perillyl alcohol. Rejuvenation Res. 2014 Apr;17(2):145-9.
11 de Almeida AA1, Costa JP, de Carvalho RB, de Sousa DP, de Freitas RM. Evaluation of acute toxicity of a natural compound (+)-limonene epoxide and its anxiolytic-like action. Brain Res. 2012 Apr 11;1448:56-62
12 Park HM1, Lee JH, Yaoyao J, Jun HJ, Lee SJ. Limonene, a natural cyclic terpene, is an agonistic ligand for adenosine A(2A) receptors. Biochem Biophys Res Commun. 2011 Jan 7;404(1):345-8.
Linalool
1 Toyoshi Umezua, Kimiyo Nagano, Hiroyasu Ito, Kiyomi Kosakai, Misao Sakaniwa, Masatoshi Morita. Anticonflict effects of lavender oil and identification of its active constituents. Pharmacology Biochemistry and Behavior. Volume 85, Issue 4, December 2006, Pages 713–721.
2 Elisabetsky E, Marschner J, Souza DO. Effects of Linalool on glutamatergic system in the rat cerebral cortex. Neurochem Res. 1995;20:461–465.
3 do Socorro SRMS, Mendonca-Filho RR, Bizzo HR, de Almeida Rodrigues I, Soares RM, Souto-Padron T, et al. Antileishmanial activity of a linalool-rich essential oil from Croton cajucara. Antimicrob Agents Chemother. 2003;47:1895–1901.
4 Tanida M, Niijima A, Shen J, Nakamura T, Nagai K. Olfactory stimulation with scent of lavender oil affects autonomic neurotransmission and blood pressure in rats. Neurosci Lett. 2006 May 1;398(1-2):155-60.
5 Kim JT, Ren CJ, Fielding GA, Pitti A, Kasumi T, Wajda M, et al. Treatment with lavender aromatherapy in the post-anesthesia care unit reduces opioid requirements of morbidly obese patients undergoing laparoscopic adjustable gastric banding. Obes Surg. 2007;17:920–925.
6 Loizzo MR, Tundis R, Menichini F, Saab AM, Statti GA, and Menichini F. Antiproliferative effects of essential oils and their major constituents in human renal adenocarcinoma and amelanotic melanoma cells. Cell Prolif. 2008 Dec;41(6):1002-12.
7 Ravizza R, Gariboldi MB, Molteni R, Monti E. Linalool, a plant-derived monoterpene alcohol, reverses doxorubicin resistance in human breast adenocarcinoma cells. Oncol Rep. 2008 Sep;20(3):625-30.
8 Chiang LC, Chiang W, Chang MY, Ng LT, and Lin CC. Antileukemic activity of selected natural products in Taiwan. Am J Chin Med. 2003;31(1):37-46.
9 Angélica Maria Sabogal-Guáqueta, Edison Osorio, and Gloria Patricia Cardona-Gómez. Linalool reverses neuropathological and behavioral impairments in old triple transgenic Alzheimer's mice. Neuropharmacology. Volume 102, March 2016, Pages 111–120.
10 Jianqun Ma, Hai Xu, Jun Wu, Changfa Qu, Fenglin Sun, and Shidong Xu. Linalool inhibits cigarette smoke-induced lung inflammation by inhibiting NF-κB activation. International Immunopharmacology. Volume 29, Issue 2, December 2015, Pages 708–713.
11 Buchbauer G, Jirovetz L, Jager W, Plank C, Dietrich H. Fragrance compounds and essential oils with sedative effects upon inhalation. J Pharm Sci. 1993;82:660–664.
12 Russo EB. Handbook of Psychotropic Herbs: A Scientific Analysis of Herbal Remedies for Psychiatric Conditions. Binghamton, NY: Haworth Press; 2001.
Myrcene
1 do Vale TG, Furtado EC, Santos JG, Jr, Viana GS. Central effects of citral, myrcene and limonene, constituents of essential oil chemotypes from Lippia alba (Mill.) n.e. Brown. Phytomed. 2002;9:709–714.
2 Lorenzetti BB, Souza GE, Sarti SJ, Santos Filho D, Ferreira SH. Myrcene mimics the peripheral analgesic activity of lemongrass tea. J Ethnopharmacol. 1991;34:43–48
3 Rao VS, Menezes AM, Viana GS. Effect of myrcene on nociception in mice. J Pharm Pharmacol. 1990;42:877–878.
4 Bonamin F, Moraes TM, Dos Santos RC, Kushima H, Faria FM, Silva MA, Junior IV, Nogueira L, Bauab TM, Souza Brito AR, da Rocha LR, Hiruma-Lima CA. The effect of a minor constituent of essential oil from Citrus aurantium: The role of β-myrcene in preventing peptic ulcer disease. Chem Biol Interact. 2014;212:11-9.
Pinene
1 Falk AA, Hagberg MT, Lof AE, Wigaeus-Hjelm EM, Wang ZP. Uptake, distribution and elimination of alpha-pinene in man after exposure by inhalation. Scand J Work Environ Health. 1990;16:372–378.
2 Rivas da Silva AC1, Lopes PM, Barros de Azevedo MM, Costa DC, Alviano CS, Alviano DS. Biological activities of α-pinene and β-pinene enantiomers. Molecules. 2012 May 25;17(6):6305-16.
3 Perry NS, Houghton PJ, Theobald A, Jenner P, Perry EK. In-vitro inhibition of human erythrocyte acetylcholinesterase by salvia lavandulaefolia essential oil and constituent terpenes. J Pharm Pharmacol. 2000;52:895–902.
4 Weiqiang Chena, Ying Liua, Ming Lia, Jianwen Maoa, Lirong Zhanga, Rongbo Huanga, Xiaobao Jina, and Lianbao Yeb. Anti-tumor effect of α-pinene on human hepatoma cell lines through inducing G2/M cell cycle arrest. Journal of Pharmacological Sciences
Volume 127, Issue 3, March 2015, Pages 332–338.
Terpineol
1 Williams AC, Barry BW : Terpenes and the lipid-protein-partitioning theory of skin penetration enhancement. Pharm Res 8(1): 17-24, 1991.
2 Saadia Bashir Hassan, Hala Gali-Muhtasib, Hanna Göransson and Rolf Larsson. Alpha Terpineol: A Potential Anticancer Agent which Acts through Suppressing NF-κB Signalling. Anticancer Research June 2010 vol. 30 no. 6 1911-1919.
3 Lampronti I, Saab AM, Gambari R : Antiproliferative activity of essential oils derived from plants belonging to the Magnoliophyta division. Int J Oncol 29(4): 989-995, 2006.
Terpinolene
1 Ito K and Ito M. The sedative effect of inhaled terpinolene in mice and its structure-activity relationships. Journal of Natural Medicines. Jan 2013, 67(4):833-837.
2 Okumura N, Yoshida H, Nishimura Y, Kitagishi Y, and Matsuda S. Terpinolene, a component of herbal sage, downregulates AKT1 expression in K562 cells. Oncol Lett. 2012 Feb;3(2):321-324.
Caryophyllene
1 Gertsch J, Leonti M, Raduner S, et al. Beta-caryophyllene is a dietary cannabinoid. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(26):9099-9104.
2 de Oliveira CC, de Oliveira CV, Grigoletto J, Ribeiro LR, Funck VR, Grauncke AC, de Souza TL, Souto NS, Furian AF, Menezes IR, Oliveira MS. Anticonvulsant activity of β-caryophyllene against pentylenetetrazol-induced seizures. Epilepsy Behav. 2016 Mar;56:26-31.
3 Santos NA, Martins NM, Sisti FM, Fernandes LS, Ferreira RS, de Freitas O, Santos AC. The cannabinoid beta-caryophyllene (BCP) induces neuritogenesis in PC12 cells by a cannabinoid-receptor-independent mechanism. Chem Biol Interact. 2016 Nov 18;261:86-95.
4 Cheng Y, Dong Z, Liu S. β-Caryophyllene ameliorates the Alzheimer-like phenotype in APP/PS1 Mice through CB2 receptor activation and the PPARγ pathway. Pharmacology. 2014;94(1-2):1-12.
5 Jie Lou, Zhipeng Teng, Liangke Zhang, Jiadan Yang, Lianju Ma, Fang Wang, Xiaocui Tian, Ruidi An, Mei Yang, Qian Zhang, Lu Xu, and Zhi Dong. β-Caryophyllene/Hydroxypropyl-β-Cyclodextrin Inclusion Complex Improves Cognitive Deficits in Rats with Vascular Dementia through the Cannabinoid Receptor Type 2 -Mediated Pathway. Front. Pharmacol., 19 January 2017. https://doi.org/10.3389/fphar.2017.00002
6 Tung Y.‐T., Chua M.‐T., Wang S.‐Y., and Chang S.‐T.. 2008. Anti‐inflammation activities of essential oil and its constituents from indigenous cinnamon (Cinnamomum osmophloeum) twigs. Bioresour. Technol. 99:3908–3913.
7 Bento AF, Marcon R, Dutra RC, Claudino RF, Cola M, Leite DF, Calixto JB. β-Caryophyllene inhibits dextran sulfate sodium-induced colitis in mice through CB2 receptor activation and PPARγ pathway. Am J Pathol. 2011 Mar;178(3):1153-66.
8 Andrade-Silva M, Correa LB, Candéa AL, Cavalher-Machado SC, Barbosa HS, Rosas EC, Henriques MG. The cannabinoid 2 receptor agonist β-caryophyllene modulates the inflammatory reaction induced by Mycobacterium bovis BCG by inhibiting neutrophil migration. Inflamm Res. 2016 Nov;65(11):869-879.
9 Dahham SS, Tabana YM, Iqbal MA, Ahamed MB, Ezzat MO, Majid AS, Majid AM. The Anticancer, Antioxidant and Antimicrobial Properties of the Sesquiterpene β-Caryophyllene from the Essential Oil of Aquilaria crassna. Molecules. 2015 Jun 26;20(7):11808-29.
10 Sabulal B., Dan M., Kurup R., Pradeep N. S., Valsamma R. K., and George V.. 2006. Caryophyllene‐rich rhizome oil of Zingiber nimmonii from South India: chemical characterization and antimicrobial activity. Phytochemistry 67:2469–2473.
11 Suijun W, Zhen Y, Ying G, Yanfang W. A role for trans-caryophyllene in the moderation of insulin secretion. Biochem Biophys Res Commun. 2014 Feb 21;444(4):451-4.
12 Dahham S. S., Tabana Y. M., Iqbal M. A., Ahamed M. B., Ezzat M. O., Majid A. S., et al. 2015. The Anticancer, antioxidant and antimicrobial properties of the Sesquiterpene β‐Caryophyllene from the essential Oil of Aquilaria crassna . Molecules 20:11808–11829.
13 Jung J. I., Kim E. J., Kwon G. T., Jung Y. J., Park T., Kim Y., et al. 2015. β‐Caryophyllene potently inhibits solid tumor growth and lymph node metastasis of B16F10 melanoma cells in high‐fat diet‐induced obese C57BL/6N mice. Carcinogenesis 36:1028–1039.
14 Dahham SS, Tabana YM, Iqbal MA, Ahamed MB, Ezzat MO, Majid AS, Majid AM. The Anticancer, Antioxidant and Antimicrobial Properties of the Sesquiterpene β-Caryophyllene from the Essential Oil of Aquilaria crassna. Molecules. 2015 Jun 26;20(7):11808-29.
15 Fidyt K, Fiedorowicz A, Strządała L, Szumny A. β‐caryophyllene and β‐caryophyllene oxide—natural compounds of anticancer and analgesic properties. Cancer Medicine. 2016;5(10):3007-3017.
16 Legault J., Pichette A. Potentiating effect of beta-caryophyllene on anticancer activity of alpha-humulene, isocaryophyllene and paclitaxel. J Pharm Pharmacol. 2007 Dec;59(12):1643-7.
17 Loizzo MR, Tundis R, Menichini F, Saab AM, Statti GA, and Menichini F. Antiproliferative effects of essential oils and their major constituents in human renal adenocarcinoma and amelanotic melanoma cells. Cell Prolif. 2008 Dec;41(6):1002-12.
18 Klauke A.‐L., Racz I., Pradier B., Markert A., Zimmer A., Gertsch J., et al. 2014. The cannabinoid CB 2 receptor‐selective phytocannabinoid beta‐caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain. Eur. Neuropsychopharmacol. 24:608–620.
19 Fidyt K, Fiedorowicz A, Strządała L, Szumny A. β-caryophyllene and β-caryophyllene oxide-natural compounds of anticancer and analgesic properties. Cancer Med. 2016 Oct;5(10):3007-3017.
20 Dahham SS, Tabana YM, Iqbal MA, Ahamed MB, Ezzat MO, Majid AS, Majid AM. The Anticancer, Antioxidant and Antimicrobial Properties of the Sesquiterpene β-Caryophyllene from the Essential Oil of Aquilaria crassna. Molecules. 2015 Jun 26;20(7):11808-29.
21 Kamikubo R, Kai K, Tsuji-Naito K, Akagawa M. β-Caryophyllene attenuates palmitate-induced lipid accumulation through AMPK signaling by activating CB2 receptor in human HepG2 hepatocytes. Mol Nutr Food Res. 2016 Oct;60(10):2228-2242.
22 Zoltan V. Varga, Csaba Matyas, Katalin Erdelyi, Resat Cinar, Daniela Nieri, Andrea Chicca, Balazs Tamas Nemeth, Janos Paloczi, Tamas Lajtos, Lukas Corey, Gyorgy Hasko, Bin Gao, George Kunos, Jürg Gertsch, Pal Pacher. Beta-caryophyllene protects against alcoholic steatohepatitis by attenuating inflammation and metabolic dysregulation in mice. British Journal of Pharmacology. Accepted manuscript online: 20 January 2017.
23 Varga ZV, Matyas C, Erdelyi K, Cinar R, Nieri D, Chicca A, Nemeth BT, Paloczi J, Lajtos T, Corey L, Hasko G, Gao B, Kunos G, Gertsch J, Pacher P. Beta-caryophyllene protects against alcoholic steatohepatitis by attenuating inflammation and metabolic dysregulation in mice. Br J Pharmacol. 2017 Jan 20. doi: 10.1111/bph.13722.
24 Pieri FA, Souza MC, Vermelho LL, Vermelho ML, Perciano PG, Vargas FS, Borges AP, da Veiga-Junior VF, Moreira MA. Use of β-caryophyllene to combat bacterial dental plaque formation in dogs. BMC Vet Res. 2016 Oct 1;12(1):216.
25 Bahi A, Al Mansouri S, Al Memari E, Al Ameri M, Nurulain SM, Ojha S. β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice. Physiol Behav. 2014 Aug;135:119-24.
Caryophyllene Oxide
1 Fidyt K, Fiedorowicz A, Strządała L, Szumny A. β-caryophyllene and β-caryophyllene oxide-natural compounds of anticancer and analgesic properties. Cancer Med. 2016 Oct;5(10):3007-3017.
2 Jun N. J., Mosaddik A., Moon J. Y., Jang K.‐C., Lee D.‐S., Ahn K. S., et al. 2011. Cytotoxic activity of β‐caryophyllene oxide isolated from Jeju Guava (Psidium cattleianum Sabine) leaf. Rec. Nat. Prod.5:242–246.
3 Shahwar D., Ullah S., Khan M. A., Ahmad N., Saeed A., and Ullah S.. 2015. Anticancer activity of Cinnamon tamala leaf constituents towards human ovarian cancer cells. Pak. J.Pharm. Sci. 28:969–972.
4 Legault J, and Pichette A. Potentiating effect of beta-caryophyllene on anticancer activity of alpha-humulene, isocaryophyllene and paclitaxel. J Pharm Pharmacol. 2007 Dec;59(12):1643-7.
5 Kyung-Ran Park, Dongwoo Nam, Hyung-Mun Yun, Seok-Geun Lee, Hyeung-Jin Jang, Gautam Sethi, Somi K. Cho, Kwang Seok Ahn. b-Caryophyllene oxide inhibits growth and induces apoptosis through the suppression of PI3K/AKT/mTOR/S6K1 pathways and ROS-mediated MAPKs activation. Cancer Letters 312 (2011) 178–188.
6 Depo Yang, Laura Michel, Jean-Pierre Chaumont and Joelle Millet-Clere. Use of caryophellene oxide as an anti-fungal agent in an in vitro experimental model of onychomycosis. Mycopathologia 148: 79-82, 1999.
Humulene
1 Chaves JS, Leal PC, Pianowisky L, and Calixto JB. Pharmacokinetics and tissue distribution of the sesquiterpene alpha-humulene in mice. Planta Med. 2008 Nov;74(14):1678-83.
Nerolidol
1 Binet L, Binet P, Miocque M, Roux M, Bernier A. Recherches sur les proprietes pharmcodynamiques (action sedative et action spasmolytique) de quelques alcools terpeniques aliphatiques. Ann Pharm Fr. 1972;30:611–616.
2 Lee SJ, Han JI, Lee GS, Park MJ, Choi IG, Na KJ, Jeung EB. Antifungal effect of eugenol and nerolidol against Microsporum gypseum in a guinea pig model. Biol Pharm Bull. 2007 Jan;30(1):184-8.
3 Mahmoud AbouLailaa, Thillaiampalam Sivakumara, Naoaki Yokoyamaa, Ikuo Igarashia. Inhibitory effect of terpene nerolidol on the growth of Babesia parasites. Parasitology International. Volume 59, Issue 2, June 2010, Pages 278–282.
4 Lopes NP, Kato MJ, Andrade EH, Maia JG, Yoshida M, Planchart AR, et al. Antimalarial use of volatile oil from leaves of Virola surinamensis (Rol.) Warb. by Waiapi Amazon Indians. J Ethnopharmacol. 1999;67:313–319.
5 Brehm-Stecher BF, Johnson EA. Sensitization of Staphylococcus aureus and Escherichia coli to Antibiotics by the Sesquiterpenoids Nerolidol, Farnesol, Bisabolol, and Apritone. Antimicrobial Agents and Chemotherapy. 2003;47(10):3357-3360.
Phytol
1 Camila Carolina de Menezes Patrício Santos, Mirian Stiebbe Salvadori, Vanine Gomes Mota, Luciana Muratori Costa, Antonia Amanda Cardoso de Almeida, Guilherme Antônio Lopes de Oliveira, Jéssica Pereira Costa, Damião Pergentino de Sousa, Rivelilson Mendes de Freitas, and Reinaldo Nóbrega de Almeida. Antinociceptive and Antioxidant Activities of Phytol In Vivo and In Vitro Models. Neuroscience Journal. Volume 2013 (2013), Article ID 949452, 9 pages.
2 Silva RO, Sousa FB, Damasceno SR, Carvalho NS, Silva VG, Oliveira FR, Sousa DP, Aragão KS, Barbosa AL, Freitas RM, and Medeiros JV. Phytol, a diterpene alcohol, inhibits the inflammatory response by reducing cytokine production and oxidative stress. Fundam Clin Pharmacol. 2014 Aug;28(4):455-64.
3 Y. Inoue, T. Hada, A. Shiraishi, K. Hirose, H. Hamashima, and S. Kobayashi, “Biphasic effects of geranylgeraniol, teprenone, and phytol on the growth of Staphylococcus aureus,” Antimicrobial Agents and Chemotherapy, vol. 49, no. 5, pp. 1770–1774, 2005.
4 Josué de Moraes, Rosimeire N. de Oliveira, Jéssica P. Costa, Antonio L. G. Junior, Damião P. de Sousa, Rivelilson M. Freitas, Silmara M. Allegretti, and Pedro L. S. Pinto. Phytol, a Diterpene Alcohol from Chlorophyll, as a Drug against Neglected Tropical Disease Schistosomiasis Mansoni. PLoS Negl Trop Dis 8(1): e2617.
5 Josué de Moraes, R. N. et al.
6 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.
CBC
1 D. J. Harvey, Proc. Oxford Symp. Cannabis, 1985, 23–30.
2 A. A. Izzo, F. Borrelli, R. Capasso, V. Di Marzo and R. Mechoulam. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol. Sci., 2009, 30, 515–527.
3 L. De Petrocellis, V. Vellani, A. Schiano-Moriello, P. Marini, P. C. Magherini, P. Orlando and V. Di Marzo. Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. J. Pharmacol. Exp. Ther., 2008, 325, 1007–1015.
4 El-Alfy, Abir T. et al. “Antidepressant-like Effect of Δ9-Tetrahydrocannabinol and Other Cannabinoids Isolated from Cannabis Sativa L.” Pharmacology, biochemistry, and behavior 95.4 (2010): 434–442.
5 Appendino G1, Gibbons S, Giana A, Pagani A, Grassi G, Stavri M, Smith E, Rahman MM. Antibacterial cannabinoids from Cannabis sativa: a structure-activity study. J Nat Prod. 2008 Aug;71(8):1427-30.
CBD and CBDA
1 Andrew Irving, Ghayth Abdulrazzaq, Sue L.F. Chan, June Penman, Jenni Harvey, and Stephen P.H. Alexander. Cannabinoid Receptor-Related Orphan G Protein-Coupled Receptors. Advances in Pharmacology. Available online. June 12, 2017.
2 Ibid.
3 Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker E. Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn Schmiedebergs Arch Pharmacol. 2006 Feb;372(5):354-61.
4 Appendino G1, Gibbons S, Giana A, Pagani A, Grassi G, Stavri M, Smith E, Rahman MM. Antibacterial cannabinoids from Cannabis sativa: a structure-activity study. J Nat Prod. 2008 Aug;71(8):1427-30.
5 Ramer R, Heinemann K, Merkord J, Rohde H, Salamon A, Linnebacher M, Hinz B. COX-2 and PPAR-γ confer cannabidiol-induced apoptosis of human lung cancer cells. Mol Cancer Ther. 2013 Jan;12(1):69-82.
6 Costa B, Giagnoni G, Franke C, Trovato AE, Colleoni M. Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation. British Journal of Pharmacology. 2004;143(2):247-250.
7 Sean D. McAllister, Rigel T. Christian, Maxx P. Horowitz, Amaia Garcia and Pierre-Yves Desprez. Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells. Mol Cancer Ther 2007;6(11):2921–7.
8 Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol. 2001;134:845–852.
9 Costa B, Giagnoni G, Franke C, Trovato AE, Colleoni M. Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation. British Journal of Pharmacology. 2004;143(2):247-250.
10 Oláh A, Tóth BI, Borbíró I, et al. Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes. The Journal of Clinical Investigation. 2014;124(9):3713-3724.
11 Williams AC, Barry BW : Terpenes and the lipid-protein-partitioning theory of skin penetration enhancement. Pharm Res 8(1): 17-24,
12 Santos NA, Martins NM, Sisti FM, Fernandes LS, Ferreira RS, Queiroz RH, and Santos AC. The neuroprotection of cannabidiol against MPP+-induced toxicity in PC12 cells involves trkA receptors, upregulation of axonal and synaptic proteins, neuritogenesis, and might be relevant to Parkinson's disease. Toxicol In Vitro. 2015 Dec 25;30(1 Pt B):231-40.
13 Sagredo O, García-Arencibia M, de Lago E, Finetti S, Decio A, and Fernández-Ruiz J. Cannabinoids and neuroprotection in basal ganglia disorders. Mol Neurobiol. 2007 Aug;36(1):82-91.
14 Sandeep Vasant More and Dong-Kug. Promising cannabinoid-based therapies for Parkinson’s disease: motor symptoms to neuroprotection. Mol Neurodegener. 2015; 10: 17.
15 Campos AC, Fogaça MV, Sonego AB, and Guimarães FS. Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol Res. 2016 Oct;112:119-127.
16 Belén G. Ramirez, Cristina Blazquez, Teresa Gomez del Pulgar, Manuel Guzman, and Marıa L. de Ceballos. Prevention of Alzheimer’s Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation. The Journal of Neuroscience, February 23, 2005 • 25(8):1904 –1913.
17 A. J. Hampson, M. Grimaldi, J. Axelrod, and D. Wink. Cannabidiol and (−)Δ9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A. 1998 Jul 7; 95(14): 8268–8273.
18 Hampson A. J.et al.
19 Tzadok M, Uliel-Siboni S, Linder I, Kramer U, Epstein O, Menascu S, Nissenkorn A, Yosef OB, Hyman E, Granot D, Dor M, Lerman-Sagie T, and Ben-Zeev B. CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience. Seizure. 2016 Feb;35:41-4.
20 Gofshteyn JS, Wilfong A, Devinsky O, Bluvstein J, Charuta J, Ciliberto MA, Laux L, and Marsh ED. Cannabidiol as a Potential Treatment for Febrile Infection-Related Epilepsy Syndrome (FIRES) in the Acute and Chronic Phases. J Child Neurol. 2017 Jan;32(1):35-40.
21 Lippiello P, Balestrini S, Leo A, Coppola A, Citraro R, Elia M, Russo E, and De Sarro G. From Cannabis to Cannabidiol to Treat Epilepsy, Where Are We? Curr Pharm Des. 2016;22(42):6426-6433.
22 Reddy DS, and Golub VM. The Pharmacological Basis of Cannabis Therapy for Epilepsy. J Pharmacol Exp Ther. 2016 Apr;357(1):45-55.
23 Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, Miller I, Flamini R, Wilfong A, Filloux F, Wong M, Tilton N, Bruno P, Bluvstein J, Hedlund J, Kamens R, Maclean J, Nangia S, Singhal NS, Wilson CA, Patel A, Cilio and MR. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016 Mar;15(3):270-8.
24 Orrin Devinsky, Joseph Sullivan, Daniel Friedman, Elizabeth Thiele, Eric Marsh, Linda Laux, Julie Hedlund, Nicole Tilton, Judith Bluvstein and Maria Cilio. Efficacy And Safety of Epidiolex (Cannabidiol) in Children and Young Adults with Treatment-Resistant Epilepsy: Initial Data From an Expanded Access Program. American Epilepsy Society. Annual Meeting Abstracts: View. (Abst. 3.303), 2014.
25 Leonardo BM Resstel, Rodrigo F Tavares, Sabrina FS Lisboa, Sâmia RL Joca, Fernando MA Corrêa, and Francisco S Guimarães. 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol. 2009 Jan; 156(1): 181–188.
26 Nalivaiko E, Ootsuka Y, Blessing WW. "Activation of 5-HT1A receptors in the medullary raphe reduces cardiovascular changes elicited by acute psychological and inflammatory stresses in rabbits". Am J Physiol Regul Integr Comp Physiol. (2005). 289 (2): R596–R604.
27 G.A. Kennett , C.T. Dourish 1, G. Curzon. Antidepressant-like action of 5-HT1A agonists and conventional antidepressants in an animal model of depression. European Journal of Pharmacology Volume 134, Issue 3, 24 February 1987, Pages 265-274.
28 Popova, N.K. et al. Involvement of the 5-HT1A and 5-HT1B serotonergic receptor subtypes in sexual arousal in male mice. Psychoneuroendocrinology , Volume 27 , Issue 5 , 609 – 618.
29 Shannon S, and Opila-Lehman J. Effectiveness of Cannabidiol Oil for Pediatric Anxiety and Insomnia as Part of Posttraumatic Stress Disorder: A Case Report. Perm J. 2016 Fall;20(4):108-111.
30 Lee JLC, Bertoglio LJ, Guimarães FS, Stevenson CW. Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorders. Br J Pharmacol. 2017;174(19):3242-3256.
31 Campos AC, Fogaça MV, Sonego AB2, and Guimarães FS. Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol Res. 2016 Oct;112:119-127.
32 Alline Cristina Campos, Fabricio Araújo Moreira, Felipe Villela Gomes, Elaine Aparecida Del Bel, and Francisco Silveira Guimarães. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond B Biol Sci. 2012 Dec 5;367(1607):3364-78.
33 Moldzio R1, Pacher T, Krewenka C, Kranner B, Novak J, Duvigneau JC, and Rausch WD. Effects of cannabinoids Δ(9)-tetrahydrocannabinol, Δ(9)-tetrahydrocannabinolic acid and cannabidiol in MPP+ affected murine mesencephalic cultures. Phytomedicine. 2012 Jun 15;19(8-9):819-24.
34 Lucia Renee Ruhaak, Jenny Felth, Pernilla Christina Karlsson, Joseph James Rafter, Robert Verpoorte, and Lars Bohlin. Evaluation of the Cyclooxygenase Inhibiting Effects of Six Major Cannabinoids Isolated from Cannabis sativa. Biol. Pharm. Bull. 34(5) 774—778 (2011).
35 D Bolognini, EM Rock, NL Cluny, MG Cascio, CL Limebeer, M Duncan, CG Stott, FA Javid, LA Parker, and RG Pertwee. Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation. Br J Pharmacol. 2013 Mar; 168(6): 1456–1470.
36 Rock EM, Limebeer CL, Navaratnam R, Sticht MA, Bonner N, Engeland K, Downey R, Morris H, Jackson M, and Parker LA. A comparison of cannabidiolic acid with other treatments for anticipatory nausea using a rat model of contextually elicited conditioned gaping. Psychopharmacology (Berl). 2014 Aug;231(16):3207-15.
CBG
1 Oláh A, Markovics A, Szabó-Papp J, Szabó PT, Stott C, Zouboulis CC, Bíró T. Differential effectiveness of selected non-psychotropic phytocannabinoids on human sebocyte functions implicates their introduction in dry/seborrhoeic skin and acne treatment. Exp Dermatol. 2016 Sep;25(9):701-7.
2 M. G. Cascio, L. A. Gauson, L. A. Stevenson, R. A. Ross and R. G. Pertwee. Evidence that the plant cannabinoid cannabigerol is a highly potent α2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. Br. J. Pharmacol., 2010, 159, 129–141.
3 Z. P. Khan, C. N. Ferguson and R. M. Jones. Alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role. Anaesthesia, 1999, 54, 146–165.
3 M. G. Cascio, L. A. Gauson, L. A. Stevenson, R. A. Ross and R. G. Pertwee. Evidence that the plant cannabinoid cannabigerol is a highly potent α2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. Br. J. Pharmacol., 2010, 159, 129–141.
4 Z. P. Khan, C. N. Ferguson and R. M. Jones. Alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role. Anaesthesia, 1999, 54, 146–165.
5 Appendino G1, Gibbons S, Giana A, Pagani A, Grassi G, Stavri M, Smith E, Rahman MM. Antibacterial cannabinoids from Cannabis sativa: a structure-activity study. J Nat Prod. 2008 Aug;71(8):1427-30.
6 De Petrocellis, V. Vellani, A. Schiano-Moriello, P. Marini, P. C. Magherini, P. Orlando and V. Di Marzo. Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. J. Pharmacol. Exp. Ther., 2008, 325, 1007–1015.
7 Brierley, Daniel I et al. “Cannabigerol Is a Novel, Well-Tolerated Appetite Stimulant in Pre-Satiated Rats.” Psychopharmacology 233.19 (2016): 3603–3613. PMC.
8 Brierley, D. et al.
CBN
1 Appendino G1, Gibbons S, Giana A, Pagani A, Grassi G, Stavri M, Smith E, Rahman MM. Antibacterial cannabinoids from Cannabis sativa: a structure-activity study. J Nat Prod. 2008 Aug;71(8):1427-30.
2 Noriyuki Usami, Takeshi Okuda, Hisatoshi Yoshida, Toshiyuki Kimura, Kazuhito Watanabe, Hidetoshi Yoshimura, and Ikuo Yamamoto. Synthesis and Pharmacological Evaluation in Mice of Halogenated Cannabidiol Derivatives. Chem. Pharm. Bull. 47(11) 1641—1645 (1999).
3 Takahashi RN, Karniol IG. Pharmacologic interaction between cannabinol and delta9-tetrahydrocannabinol. Psychopharmacologia. 1975;41(3):277-84.
THC and THCA
1 Martin BR. Structural requirements for cannabinoid-induced antinociceptive activity in mice. Life Sci. 1985;36:1523–1530.
2 Welch SP, Dunlow LD, Patrick GS, Razdan RK. Characterisation of anandamide-induced antinociception and cross-tolerance to delta 9-THC after intrathecal administration to mice: blockade of delta 9-THC-induced antinociception. J Pharmacol Exp Ther. 1995;273:1235–1244.
3 Nahas, G. G., N. Suciu-Foca, J.-P. Armand, and A. Morishima. 1974. Inhibition of cellular mediated immunity in marihuana smokers. Science 183:419-420.
4 Srivastava, M. D., B. I. S. Srivastava, and B. Brouhard. 1998. Δ9 tetrahydrocannabinol and cannabidiol alter cytokine production by human immune cells. Immunopharmacology 40:179-185.
5 Watzl, B., P. Scuderi, and R. R. Watson. 1991. Influence of marijuana components (THC and CBD) on human mononuclear cell cytokine secretion in vitro. Adv. Exp. Med. Biol. 288:63-70.
6 J P Hartley, S G Nogrady, and A Seaton. Bronchodilator effect of delta1-tetrahydrocannabinol. Br J Clin Pharmacol. 1978 Jun; 5(6): 523–525.
7 Tashkin DP, Shapiro BJ, Lee YE, and Harper CE. Effects of smoked marijuana in experimentally induced asthma. Am Rev Respir Dis. 1975 Sep;112(3):377-86.
8 S J Williams, J P Hartley, and J D Graham. Bronchodilator effect of delta1-tetrahydrocannabinol administered by aerosol of asthmatic patients. Thorax. 1976 Dec; 31(6): 720–723.
9 Donald P. Tashkin , Bertrand J. Shapiro , and Ira M. Frank. Acute Effects of Smoked Marijuana and Oral Δ9-Tetrahydrocannabinol on Specific Airway Conductance in Asthmatic Subjects. American Journal of Respiratory and Critical Care Medicine. Vol. 109, No. 4 | Apr 01, 1974.
10 Haney M, Gunderson EW, Rabkin J, Hart CL, Vosburg SK, Comer SD, and Foltin RW. Dronabinol and marijuana in HIV-positive marijuana smokers. Caloric intake, mood, and sleep. J Acquir Immune Defic Syndr. 2007 Aug 15;45(5):545-54.
11 Müller-Vahl KR, Schneider U, Prevedel H, Theloe K, Kolbe H, Daldrup T, and Emrich HM. Delta 9-tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6-week randomized trial. J Clin Psychiatry. 2003 Apr;64(4):459-65.
12 Tramèr MR, Carroll D, Campbell FA, Reynolds DJM, Moore RA, McQuay HJ. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ: British Medical Journal. 2001;323(7303):16.
13 Charles W Webb, MDcorresponding author and Sandra M Webb, RN, BSN. Therapeutic Benefits of Cannabis: A Patient Survey. Hawaii J Med Public Health. 2014 Apr; 73(4): 109–111.
14 Rock EM1, Kopstick RL, Limebeer CL, and Parker LA. Tetrahydrocannabinolic acid reduces nausea-induced conditioned gaping in rats and vomiting in Suncus murinus. Br J Pharmacol. 2013 Oct;170(3):641-8.
15 Moldzio R1, Pacher T, Krewenka C, Kranner B, Novak J, Duvigneau JC, and Rausch WD. Effects of cannabinoids Δ(9)-tetrahydrocannabinol, Δ(9)-tetrahydrocannabinolic acid and cannabidiol in MPP+ affected murine mesencephalic cultures. Phytomedicine. 2012 Jun 15;19(8-9):819-24.
16 Lucia Renee Ruhaak, Jenny Felth, Pernilla Christina Karlsson, Joseph James Rafter, Robert Verpoorte, and Lars Bohlin. Evaluation of the Cyclooxygenase Inhibiting Effects of Six Major Cannabinoids Isolated from Cannabis sativa. Biol. Pharm. Bull. 34(5) 774—778 (2011).