Sumner H Burstein PHD
Title Professor Emeritus
Institution University of Massachusetts Medical School
Department Biochemistry & Molecular Pharmacology
Address University of Massachusetts Medical School
364 Plantation Street, LRB
Worcester MA 01605
Telephone 508-856-2850
Email
Narrative

Academic History

BS, Massachusetts Institute of Technology, 1953
PhD, Wayne State University, 1959 Postdoctoral Training
Fellow, Weizmann Institute, 1960
Fellow, Brandeis University, 1961

The Mechanism of Action of the Cannabinoids

Photo: Sumner Burstein, PhDTherapeutically Useful Cannabinoids
Interest in the cannabinoid acid metabolites of THC was revived recently by data we obtained showing that they exhibit some of the properties that are associated with nonsteroidal antiinflammatory agents (NSAIDs). The acids being non-psychoactive, were long thought to be without any biological actions of their own. In fact, our findings support the possibility that several effects believed to be due to THC may actually be mediated by the acid metabolites. In addition to helping explain the pharmacology of THC, our findings have suggested a route to the discovery of novel NSAIDs with minimal adverse side-effects, a much sought after goal of pharmaceutical research. Using THC-7-oic acid as a template molecule, we have designed and studied several dimethylheptyl side-chain analogs that show similar antiinflammatory properties, but at doses as low as 10 to 100µg/kg p.o. The most promising candidate has been named ajulemic acid which, in addition to its antiinflammatory actions, shows analgesic properties comparable to morphine in potency but devoid of the undesireable side effects. Ajulemic acid has recently been subjected by initial trials in humans based on its generally low toxicity in a variety of in vitro and animal models, and a Phase I trial where it showed no psychotropic activity. We have also found evidence for the existence of an endogenous cannabinoid acid, NAGly, that arises from the metabolism of anandamide, the endogenous THC. Like the THC acids, NAGly shows analgesic and anti-inflammatory activity.

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Publications
1. Kattamuri PV, Salmonsen R, McQuain C, Burstein S, Sun H, Li G. Asymmetric synthesis of novel N-(1-phenyl-2,3-dihydroxypropyl)arachidonylamides and evaluation of their anti-inflammatory activity. Life Sci. 2013 Mar 19; 92(8-9):506-11.
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2. Burstein S, McQuain C, Salmonsen R, Seicol B. N-Amino acid linoleoyl conjugates: Anti-inflammatory activities. Bioorg Med Chem Lett. 2012 Jan 15; 22(2):872-5.
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3. Burstein SH, McQuain CA, Ross AH, Salmonsen RA, Zurier RE. Resolution of inflammation by N-arachidonoylglycine. J Cell Biochem. 2011 Nov; 112(11):3227-33.
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4. Tan B, O'Dell DK, Yu YW, Monn MF, Hughes HV, Burstein S, Walker JM. Identification of endogenous acyl amino acids based on a targeted lipidomics approach. J Lipid Res. 2010 Jan; 51(1):112-9.
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5. Burstein SH, Zurier RB. Cannabinoids, endocannabinoids, and related analogs in inflammation. AAPS J. 2009 Mar; 11(1):109-19.
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6. Bradshaw HB, Rimmerman N, Hu SS, Burstein S, Walker JM. Novel endogenous N-acyl glycines identification and characterization. Vitam Horm. 2009; 81:191-205.
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7. Burstein S, Salmonsen R. Acylamido analogs of endocannabinoids selectively inhibit cancer cell proliferation. Bioorg Med Chem. 2008 Nov 15; 16(22):9644-51.
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8. Stebulis JA, Johnson DR, Rossetti RG, Burstein SH, Zurier RB. Ajulemic acid, a synthetic cannabinoid acid, induces an antiinflammatory profile of eicosanoids in human synovial cells. Life Sci. 2008 Nov 7; 83(19-20):666-70.
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9. Rimmerman N, Bradshaw HB, Hughes HV, Chen JS, Hu SS, McHugh D, Vefring E, Jahnsen JA, Thompson EL, Masuda K, Cravatt BF, Burstein S, Vasko MR, Prieto AL, O'Dell DK, Walker JM. N-palmitoyl glycine, a novel endogenous lipid that acts as a modulator of calcium influx and nitric oxide production in sensory neurons. Mol Pharmacol. 2008 Jul; 74(1):213-24.
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10. Burstein S. The elmiric acids: biologically active anandamide analogs. Neuropharmacology. 2008 Dec; 55(8):1259-64.
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11. Ambrosio AL, Dias SM, Polikarpov I, Zurier RB, Burstein SH, Garratt RC. Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator-activated receptor gamma. J Biol Chem. 2007 Jun 22; 282(25):18625-33.
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12. Burstein SH, Adams JK, Bradshaw HB, Fraioli C, Rossetti RG, Salmonsen RA, Shaw JW, Walker JM, Zipkin RE, Zurier RB. Potential anti-inflammatory actions of the elmiric (lipoamino) acids. Bioorg Med Chem. 2007 May 15; 15(10):3345-55.
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13. Johnson DR, Stebulis JA, Rossetti RG, Burstein SH, Zurier RB. Suppression of fibroblast metalloproteinases by ajulemic acid, a nonpsychoactive cannabinoid acid. J Cell Biochem. 2007 Jan 1; 100(1):184-90.
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14. Burstein S. PPAR-gamma: a nuclear receptor with affinity for cannabinoids. Life Sci. 2005 Aug 19; 77(14):1674-84.
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15. Burstein S. Ajulemic acid (IP-751): synthesis, proof of principle, toxicity studies, and clinical trials. AAPS J. 2005; 7(1):E143-8.
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16. Salim K, Schneider U, Burstein S, Hoy L, Karst M. Pain measurements and side effect profile of the novel cannabinoid ajulemic acid. Neuropharmacology. 2005 Jun; 48(8):1164-71.
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17. Burstein S, Zurier RB. Pain reduction and lack of psychotropic effects with ajulemic acid: comment on the article by Sumariwalla et al. Arthritis Rheum. 2004 Dec; 50(12):4078-9; author reply 4079-80.
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18. Burstein SH, Karst M, Schneider U, Zurier RB. Ajulemic acid: A novel cannabinoid produces analgesia without a "high". Life Sci. 2004 Aug 6; 75(12):1513-22.
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19. Grazia Cascio M, Minassi A, Ligresti A, Appendino G, Burstein S, Di Marzo V. A structure-activity relationship study on N-arachidonoyl-amino acids as possible endogenous inhibitors of fatty acid amide hydrolase. Biochem Biophys Res Commun. 2004 Jan 30; 314(1):192-6.
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20. Karst M, Salim K, Burstein S, Conrad I, Hoy L, Schneider U. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA. 2003 Oct 1; 290(13):1757-62.
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21. Bidinger B, Torres R, Rossetti RG, Brown L, Beltre R, Burstein S, Lian JB, Stein GS, Zurier RB. Ajulemic acid, a nonpsychoactive cannabinoid acid, induces apoptosis in human T lymphocytes. Clin Immunol. 2003 Aug; 108(2):95-102.
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22. Liu J, Li H, Burstein SH, Zurier RB, Chen JD. Activation and binding of peroxisome proliferator-activated receptor gamma by synthetic cannabinoid ajulemic acid. Mol Pharmacol. 2003 May; 63(5):983-92.
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23. Zurier RB, Rossetti RG, Burstein SH, Bidinger B. Suppression of human monocyte interleukin-1beta production by ajulemic acid, a nonpsychoactive cannabinoid. Biochem Pharmacol. 2003 Feb 15; 65(4):649-55.
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24. Burstein SH, Huang SM, Petros TJ, Rossetti RG, Walker JM, Zurier RB. Regulation of anandamide tissue levels by N-arachidonylglycine. Biochem Pharmacol. 2002 Oct 1; 64(7):1147-50.
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25. Recht LD, Salmonsen R, Rosetti R, Jang T, Pipia G, Kubiatowski T, Karim P, Ross AH, Zurier R, Litofsky NS, Burstein S. Antitumor effects of ajulemic acid (CT3), a synthetic non-psychoactive cannabinoid. Biochem Pharmacol. 2001 Sep 15; 62(6):755-63.
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26. Huang SM, Bisogno T, Petros TJ, Chang SY, Zavitsanos PA, Zipkin RE, Sivakumar R, Coop A, Maeda DY, De Petrocellis L, Burstein S, Di Marzo V, Walker JM. Identification of a new class of molecules, the arachidonyl amino acids, and characterization of one member that inhibits pain. J Biol Chem. 2001 Nov 16; 276(46):42639-44.
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27. Burstein SH. Ajulemic acid (CT3): a potent analog of the acid metabolites of THC. Curr Pharm Des. 2000 Sep; 6(13):1339-45.
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28. Burstein SH, Rossetti RG, Yagen B, Zurier RB. Oxidative metabolism of anandamide. Prostaglandins Other Lipid Mediat. 2000 Apr; 61(1-2):29-41.
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29. Yagen B, Burstein S. Novel and sensitive method for the detection of anandamide by the use of its dansyl derivative. J Chromatogr B Biomed Sci Appl. 2000 Mar 31; 740(1):93-9.
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30. Burstein SH. The cannabinoid acids: nonpsychoactive derivatives with therapeutic potential. Pharmacol Ther. 1999 Apr; 82(1):87-96.
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31. Pestonjamasp VK, Burstein SH. Anandamide synthesis is induced by arachidonate mobilizing agonists in cells of the immune system. Biochim Biophys Acta. 1998 Nov 2; 1394(2-3):249-60.
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32. Zurier RB, Rossetti RG, Lane JH, Goldberg JM, Hunter SA, Burstein SH. Dimethylheptyl-THC-11 oic acid: a nonpsychoactive antiinflammatory agent with a cannabinoid template structure. Arthritis Rheum. 1998 Jan; 41(1):163-70.
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33. Burstein SH, Friderichs E, Kögel B, Schneider J, Selve N. Analgesic effects of 1',1' dimethylheptyl-delta8-THC-11-oic acid (CT3) in mice. Life Sci. 1998; 63(3):161-8.
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34. Hunter SA, Burstein SH. Receptor mediation in cannabinoid stimulated arachidonic acid mobilization and anandamide synthesis. Life Sci. 1997; 60(18):1563-73.
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35. Burstein SH, Young JK, Wright GE. Relationships between eicosanoids and cannabinoids. Are eicosanoids cannabimimetic agents?. Biochem Pharmacol. 1995 Nov 27; 50(11):1735-42.
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36. Burstein SH, Hunter SA. Stimulation of anandamide biosynthesis in N-18TG2 neuroblastoma cells by delta 9-tetrahydrocannabinol (THC). Biochem Pharmacol. 1995 Mar 15; 49(6):855-8.
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37. Wartmann M, Campbell D, Subramanian A, Burstein SH, Davis RJ. The MAP kinase signal transduction pathway is activated by the endogenous cannabinoid anandamide. FEBS Lett. 1995 Feb 13; 359(2-3):133-6.
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38. Burstein SH, Debatis M, Subramanian A. Cannabinoid photolabelling of a G-protein gamma-subunit in mouse peritoneal cells. Life Sci. 1995; 56(23-24):1991-8.
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39. Burstein S, Budrow J, Debatis M, Hunter SA, Subramanian A. Phospholipase participation in cannabinoid-induced release of free arachidonic acid. Biochem Pharmacol. 1994 Sep 15; 48(6):1253-64.
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40. Burstein SH, Audette CA, Breuer A, Devane WA, Colodner S, Doyle SA, Mechoulam R. Synthetic nonpsychotropic cannabinoids with potent antiinflammatory, analgesic, and leukocyte antiadhesion activities. J Med Chem. 1992 Aug 21; 35(17):3135-41.
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41. Avunduk C, Eastwood GL, Polakowski N, Burstein S. Hydrocortisone has a biphasic effect on rat gastric mucosal prostaglandin generation in vivo: inhibition at low doses, stimulation at high doses. Prostaglandins Leukot Essent Fatty Acids. 1992 Apr; 45(4):329-32.
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42. Audette CA, Burstein SH, Doyle SA, Hunter SA. G-protein mediation of cannabinoid-induced phospholipase activation. Pharmacol Biochem Behav. 1991 Nov; 40(3):559-63.
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43. Hunter SA, Audette CA, Burstein S. Elevation of brain prostaglandin E2 levels in rodents by delta 1-tetrahydrocannabinol. Prostaglandins Leukot Essent Fatty Acids. 1991 Jul; 43(3):185-90.
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44. Burstein SH, Audette CA, Charalambous A, Doyle SA, Guo Y, Hunter SA, Makriyannis A. Detection of cannabinoid receptors by photoaffinity labelling. Biochem Biophys Res Commun. 1991 Apr 15; 176(1):492-7.
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45. Perez-Reyes M, Burstein SH, White WR, McDonald SA, Hicks RE. Antagonism of marihuana effects by indomethacin in humans. Life Sci. 1991; 48(6):507-15.
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46. Burstein S. Cannabinoid induced changes in eicosanoid synthesis by mouse peritoneal cells. Adv Exp Med Biol. 1991; 288:107-12.
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47. Doyle SA, Burstein SH, Dewey WL, Welch SP. Further studies on the antinociceptive effects of delta 6-THC-7-oic acid. Agents Actions. 1990 Aug; 31(1-2):157-63.
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48. Audette CA, Burstein S. Inhibition of leukocyte adhesion by the in vivo and in vitro administration of cannabinoids. Life Sci. 1990; 47(9):753-9.
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49. Burstein SH, Audette CA, Doyle SA, Hull K, Hunter SA, Latham V. Antagonism to the actions of platelet activating factor by a nonpsychoactive cannabinoid. J Pharmacol Exp Ther. 1989 Nov; 251(2):531-5.
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50. Burstein SH, Hull K, Hunter SA, Shilstone J. Immunization against prostaglandins reduces delta 1-tetrahydrocannabinol-induced catalepsy in mice. Mol Pharmacol. 1989 Jan; 35(1):6-9.
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51. Burstein SH, Hull K, Hunter SA, Latham V. Cannabinoids and pain responses: a possible role for prostaglandins. FASEB J. 1988 Nov; 2(14):3022-6.
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52. Burstein SH. Inhibitory and stimulatory effects of cannabinoids on eicosanoid synthesis. NIDA Res Monogr. 1987; 79:158-72.
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53. Burstein S, Hunter SA, Latham V, Mechoulam R, Melchior DL, Renzulli L, Tefft RE. Prostaglandins and cannabis XV. Comparison of enantiomeric cannabinoids in stimulating prostaglandin synthesis in fibroblasts. Life Sci. 1986 Nov 10; 39(19):1813-23.
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54. Hunter SA, Burstein S, Renzulli L. Effects of cannabinoids on the activities of mouse brain lipases. Neurochem Res. 1986 Sep; 11(9):1273-88.
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55. Burstein S, Hunter SA, Latham V, Renzulli L. Prostaglandins and cannabis--XVI. Antagonism of delta 1-tetrahydrocannabinol action by its metabolites. Biochem Pharmacol. 1986 Aug 1; 35(15):2553-8.
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56. Burstein S, Hunter SA, Renzulli L. Prostaglandins and cannabis XIV. Tolerance to the stimulatory actions of cannabinoids on arachidonate metabolism. J Pharmacol Exp Ther. 1985 Oct; 235(1):87-91.
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57. Burstein S, Hunter SA, Ozman K, Renzulli L. Prostaglandins and cannabis--XIII. Cannabinoid-induced elevation of lipoxygenase products in mouse peritoneal macrophages. Biochem Pharmacol. 1984 Aug 15; 33(16):2653-6.
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58. Burstein S, Hunter SA, Ozman K. Prostaglandins and cannabis. XII. The effect of cannabinoid structure on the synthesis of prostaglandins by human lung fibroblasts. Mol Pharmacol. 1983 Jan; 23(1):121-6.
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59. Burstein S, Hunter SA, Sedor C, Shulman S. Prostaglandins and cannabis--IX. Stimulation of prostaglandin E2 synthesis in human lung fibroblasts by delta 1-tetrahydrocannabinol. Biochem Pharmacol. 1982 Jul 15; 31(14):2361-5.
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60. Burstein S, Ozman K, Burstein E, Palermo N, Smith E. Prostaglandins and cannabis--XI. Inhibition of delta 1-tetrahydrocannabinol-induced hypotension by aspirin. Biochem Pharmacol. 1982 Feb 15; 31(4):591-2.
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61. Burstein S, Hunter SA. Prostaglandins and cannabis--VIII. Elevation of phospholipase A2 activity by cannabinoids in whole cells and subcellular preparations. J Clin Pharmacol. 1981 Aug-Sep; 21(8-9 Suppl):240S-248S.
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62. Burstein S, Hunter SA, Sedor C. Further studies on the inhibition of Leydig cell testosterone production by cannabinoids. Biochem Pharmacol. 1980 Aug 1; 29(15):2153-4.
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63. Shoupe TS, Hunter SA, Burstein SH, Hubbard CD. The nature of the inhibition of cholesterol esterase by delta 1-tetrahydrocannabinol. Enzyme. 1980; 25(2):87-91.
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64. Burstein S, Hunter SA, Shoupe TS. Site of inhibition of leydig cell testosterone synthesis by delta 1-tetrahydrocannabinol. Mol Pharmacol. 1979 May; 15(3):633-40.
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65. Burstein S, Hunter SA, Shoupe TS. Cannabinoid inhibition of rat luteal cell progesterone synthesis. Res Commun Chem Pathol Pharmacol. 1979 May; 24(2):413-6.
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66. Burstein S, Hunter SA, Shoupe TS. Inhibition of cholesterol esterases by delta 1-tetrahydrocannabinol. Life Sci. 1978 Sep 4; 23(9):979-81.
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67. Dalterio S, Bartke A, Roberson C, Watson D, Burstein S. Direct and pituitary-mediated effects of delta9-THC and cannabinol on the testis. Pharmacol Biochem Behav. 1978 Jun; 8(6):673-8.
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68. Burstein S, Hunter SA, Shoupe TS, Taylor P. Cannabinoid inhibition of testosterone synthesis by mouse Leydig cells. Res Commun Chem Pathol Pharmacol. 1978 Mar; 19(3):557-60.
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69. Burstein S, Hunter SA. Prostaglandins and cannabis--VI. Release of arachidonic acid from HeLa cells by delta1-tetrahydrocannabinol and other cannabinoids. Biochem Pharmacol. 1978; 27(8):1275-80.
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70. Dalterio S, Bartke A, Burstein S. Cannabinoids inhibit testosterone secretion by mouse testes in vitro. Science. 1977 Jun 24; 196(4297):1472-3.
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71. Burstein S, Taylor P, El-Feraly FS, Turner C. Prostaglandins and cannabias-V. identification of p-vinylphenol as a potent inhibitor of prostaglandin synthesis. Biochem Pharmacol. 1976 Sep 1; 25(17):2003-4.
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72. Ben-Zvi Z, Burstein S. Transformation of delta-1-tetrahydrocannabinol (THC) by rabbit liver microsomes. Biochem Pharmacol. 1975 May 15; 24(10):1130-1.
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73. Burstein S, Varanelli C, Slade LT. Prostaglandins and cannabis-III. Inhibition of biosynthesis by essential oil components of marihuana. Biochem Pharmacol. 1975 May 1; 24(9):1053-4.
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74. Burstein S, Levin E, Varanelli C. Prostaglandins and cannabis. II. Inhibition of biosynthesis by the naturally occurring cannabinoids. Biochem Pharmacol. 1973 Nov 15; 22(22):2905-10.
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75. Kupfer D, Levin E, Burstein SH. Studies on the effects of 1 -tetrahydrocannabinol ( 1 -THC) and DDT on the hepatic microsomal metabolism of 1 -THC and other compounds in the rat. Chem Biol Interact. 1973 Jan; 6(1):59-66.
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76. Burstein SH, Kupfer D. Hydroxylation of trans- 1 -tetrahydrocannabinol by a hepatic microsomal monooxygenase. Chem Biol Interact. 1971 Aug; 3(4):316.
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77. Griffin CL, Pendleton R, Burstein S. Metabolism of cardiac glycosides--II. Cardiotoxicity of metabolites of digitoxin-7 aalpha-T. Biochem Pharmacol. 1971 Jan; 20(1):97-102.
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78. Griffin CL, Burstein SH. Metabolism of cardiac glycosides. I. Metabolism of digitoxin-7-alpha-T by normal rabbits and rabbits with heart failure. Biochem Pharmacol. 1967 Mar; 16(3):447-54.
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Keyword
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Institution
    
 
 
 
Keywords   
Tetrahydrocannabinol
Arachidonic Acids
Cannabinoids
Analgesics
Endocannabinoids
See all (335) keywords
Co-Authors  
Bidinger, Bonnie
Lian, Jane
Ross, Alonzo
Stebulis, Judith
Zurier, Robert
See all (7) people
Physical Neighbors  
Ali, Akbar
Bhyravbhatla, Balaji
Zitzewitz, Jill
Bilsel, Osman
Royer, William

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