Endocannabinoid System Cannabinoid Drugs

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1 Cannabinoid Drugs STCM Conference Bern Rudolf Brenneisen University of Bern, DKF 1 rudolf.brenneisen@dkf.unibe.ch

2 Milestones 1988: First cannabinoid receptor (rat brain) CB 1 -R [Devane et al, Mol Pharmacol 1988] All mammals, but also leeches, birds, amphibians, fishs, see urchins, mussels, etc.; but not insects. 2

3 1992: First CB 1 -R ligand (pork brain): arachidonylethanolamide, anandamide, AEA [Devane et al, Science 1992] Milestones 1993: Second cannabinoid receptor (rat spleen) CB 2 -R [Munro et al, Nature 1993] 1994: First synthetic CB 1 -R antagonist (SR A, rimonabant, Acomplia ; Sanofi) [Rinaldi-Carmona et al, FEBS Lett 1994] 1997: Second CB 1 -/CB 2 -R ligand: arachidonylglycerol, 2-AG 20?? CB 3 -R? [Stella et al, Nature 1997] 3

4 O Arachidonyl-PE N H O P O O HO Phospholipase D Phosphatidylethanolamine (PE) O O N-Acyltransferase H 2 N P OR HO O OR O OR OR OR O O OH P N(CH 3 ) 2 O O Arachidonic acid Phosphatidylcholine THC * O N H OH Arachidonylethanolamid, Anandamid, Endocannabinoid EXTRACELLULAR CB1 antagonist X (rimonabant, Acomplia ) Cannabis * Receptor EC-Carrier X Transport inhibitor * * Pharmacological tools! 4 γ G i β EC amidohydrolase α INTRACELLULAR AA Arachidonic acid X Metabolism inhibitor Ethanolamine Modulation of enzymes, neurotransmitters, ion channels * etc.

5 Eye Physiological keyplayer Brain Spinal cord Spleen Liver Leucocytes Nerve terminals Tonsils Heart Skin GIT Reproduction organs Bones 5

6 Physiological keyplayer Exocannabinoids (THC, etc.) Endocannabinoids (AEA, 2-AG, etc.) camp Acetylcholine Endorphins!! Catecholamines Glucocorticoids GABA CB 1 - and CB 2 -Receptors Leptin Na + /K + channels NMDA Prostaglandins Serotonin 6 Protein kinase Dopamine Phospholipase C

7 Directly or indirectly involved in: Effects of THC Processing of negative memories, traumas, stress Mental diseases, psychiatric disorders (schizophrenia, depression) Drug abuse Modulation of anxiety Sleep control Perception of pain Control of movement Control of food intake, appetite 7

8 Vincenzo di Marzo, Napoli ECS Research Institute: The endocannabinoid system is essential to life and it relates messages that affect how we relax, eat, sleep, forget and protect 8

9 Cannabinoid Drugs and Application Forms Nature and/or lab? Phytocannabinoids Synthetic Cannabinoids Multi-component preparations (Cannabis extracts etc.) Shotguns Mono-component preparations (dronabinol capsules etc.) Silver Bullets Modulation of Endocannabinoids and EC receptors Pharmacological effects 9

10 Cannabinoid Drugs and Application Forms Folk medicine, self-treatment: Cannabis-based medicines: Joint, tea, Sativa-Oil, Simpson Oil etc. Street Cannabis, home made. Quality and dosage not controlled. Harmful or inefficient application modes. Evidence-based medicine: 10 Cannabinoid-based medicines THC (dronabinol, Marinol ), nabilone (Cesamet ), CBD. Cannabis-based medicines Standardized extracts (Sativex, nabiximols) and buds (Bedrobinol ). Established galenic formulations, formula magistralis preparations. Quality and dosage controlled. Less harmful and more efficient application forms.

11 Cannabinoid Drugs and Application Forms Galenic formulation Bioavailability Effect Cannabis cigarette (smoke) % rapid Cannabis inhalation aerosol (vapor) rapid Cannabis sublingual spray >90 slow Cannabis capsule? slow Cannabis tea low slow Cannabis oil? slow THC capsule 5-20 slow THC drops 5-20 slow THC suppository rel. rapid THC patch?? THC injection solution 100 very rapid 11

12 Cannabinoid Drugs and Application Forms Pocket-size vaporizer devices In vitro validation [%] [Lanz C, DKF 2013, unpublished] 12

13 Cannabinoid Drugs and Application Forms Options and Visions Folk medicine, self-treatment without prescription: Access to Medicinal Cannabis with quality certificate Preferably using validated home recipes and harmless application forms (vaporizer) No criminalization of patient, even if not (yet) compatible with law. Academic medicine, controlled treatment with prescription: Swissmedic approved drugs (TBMs and CBMs) Medicinal Cannabis from licensed producers and suppliers, i.e. public pharmacies Pharmacopoeia monographs Optimized, patient-individualized formulations, formula magistralis, respecting GMP. 13

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