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Cannabis

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Cannabis biology

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Cannabis

  1. 1. William B. O'Shaughnessy 400 Cannabis cultivated for the first time in England at Old Buckeham Mare. 1563: Elizabeth I orders people with more than 60 acres of land to grow cannabis/hemp or be fined 1841: W.B. O’Shaughnessy an Irish medic working for British Army in India introduces cannabis to western medicine 1928. The Dangerous Drugs Act 1925 becomes law and Cannabis is made illegal in UK, 1971: Misuse of Drugs Act 1971. “Cannabis has no medical use!” and is removed for UK pharmacopeia. Cannabis a Schedule B Drug 2004: Cannabis Rescheduled to Class C (2 years unlimited fine/up to 14 years for supply) 2009: Cannabis Rescheduled to Class B (5 years unlimited fine/up to 14 years for supply) 2010: Sativex medical cannabis licensed in UK HISTORY OF (MEDICAL) CANNABIS IN UK
  2. 2. MEDICAL CANNABIS PwMS Tell us that Cannabis Helps Alleviate Symptoms (Pain & Spasticity) of Multiple Sclerosis: Evidence from Understanding the Biology of Cannabis and the Disease 2. BIOLOGY 1. ANECDOTE Why should we think about using Cannabis to treat Multiple Sclerosis?
  3. 3. UCL-INSTITUTE OF NEUROLOGY Queen Square BIOLOGY OF MULTIPLE SCLEROSIS SYMPTOMS OF MULTIPLE SCLEROSIS BLINDNESS NYSTAGMUS FATIGUE PAIN TREMOR SPASMS & SPASTICITY BLADDER PROBLEMS INCONTINENCE SEXUAL PROBLEMS COGNITIVE DEFICITS MOTOR (MOVEMENT) DEFICITS NEUROTRANSMISSION PROBLEMS Conduction Block Demyelination Loss of Axons and Neurons Loss of Synaptic Plasticity THE NATURE OF THE SYMPTOMS DEPEND ON THE LOCATION OF LESIONS WITHIN THE NEURAL CIRCUITARY
  4. 4. TOO MUCH NERVE EXCITATION TOO LITTLE NERVE INHIBITION SPASTICITY= MUSCLE STIFFNESS Damage due to Multiple Sclerosis causes: Treatment = Boost Inhibitory Signals Baclofen (Arbaclofen) GABApentin Benzodiazepines SIDE-EFFECTS= SEDATION Treatment = Block Excitatory Signals Nabiximols (Sativex) Tizanidine Anti-Convulsants SIDE-EFFECTS= SEDATION Inhibitory Nerve Red = abundant CB1 receptors Black = moderately abundant CB1 receptorsBIOLOGY OF CANNABINOID SYSTEM
  5. 5. BaclofenDantrolene Corticospinal Tract Benzodiazepine TizanidineInhibitory Interneuron Muscle CONTROL Of SPASMS Action Potential GABA α2 α2 Motor Neuron AMPA GABA A GABA B UCL-INSTITUTE OF NEUROLOGY Queen Square BIOLOGY OF MULTIPLE SCLEROSIS
  6. 6. CANNABIS (Cannabis sativa) Some varieties (HEMP) used for making: rope, paper, cloth (canvas) & oil Other varieties (described as dope, marijuana, weed, grass, hashish, resin) used as a medical and more importantly a recreational drug. Cannabis Sativa MALE Cannabis Sativa FEMALE Bract Glandular BIOLOGY OF CANNABINOID SYSTEM
  7. 7. Cannabinol (CBN) Cannabigerol (CBG) Cannabidiol (CBD) Epidiolex Tetrahydrocannabinol (THC) Cannabis plant can contains over 113 cannabinoid chemicals Major Psychoactive Ingredient Major Non-Psychoactive Ingredient BIOLOGY OF CANNABINOID SYSTEM
  8. 8. E LL M * CB1 Receptor CB2 Receptor Immune System PMN B cells Monocytes Spleen Tonsils CB2CB1 Brain Adipose Tissue Muscle Liver GI Tract Pancreas Nervous System OH O THC Plant Cannabinoids N H OH O Anandamide: Endocannabinoids BIOLOGY OF CANNABINOID SYSTEM O OH O 2-Arachidonoyl Glycerol
  9. 9. Red = abundant CB1 receptors Black = moderately abundant CB1 receptors The Function of the Brain Area where the Cannabis Receptor is located Will Determine the Effect That occurs Following Cannabis Use BIOLOGY OF CANNABINOID SYSTEM CB1R Imaging Hippocampus Learning, Memory Amygdala Emotion, Fear Cerebellum Movement Striatum Globus Pallidus Substantia Nigra Caudate Nucleus Putamen Balance & Movement Cerebral Cortex Cognitive Functions
  10. 10. Cannabinoid control of Nerve Impulse Transmission Glu=Glutamate Ca2+ = calcium Ion MS Health Synapse Red = abundant CB1 receptors Black = moderately abundant CB1 receptorsBIOLOGY OF CANNABINOID SYSTEM
  11. 11. Time Post-Injection (Min) 0 10 20 30 40 50 60 70 80 90 100 110 120 ChangeinHindlimbStiffness(%)±SEM -50 -40 -30 -20 -10 0 10 20 Sativex Vehicle CB RECEPTOR STIMULATION CAN INHIBIT TREMOR & SPASTICITY IN MODEL OF MS Cannabis + THC + CB1R Stimulators + THC-free Cannabis - CB BLOCKADE TRANSIENTLY WORSENS SPASTICITY Stimulators of + Endocannabinoids Sativex® Biological Drug Substances inhibits Experimental Spasticity P<0.001 compared to baseline BIOLOGY OF CANNABINOIDS
  12. 12. CHANGES OF SPASTICITY SCORES -0.4 -0.2 0 0.2 0.4 0.6 0.8 W eek 0 W eek 1 W eek 2 W eek 3 W eek 4 W eek 5 W eek 6 W eek 7 W eek 8 W eek 9 W eek 10 W eek 11W eek 12 LO C F Sativex Placebo P<0.0002 DeteriorationinSpasticityScore Placebo Sativex CANNABINOIDS IN THE CLINIC Novotna et al. 2011
  13. 13. CANNABINOIDS IN THE CLINIC Nabiximols (Sativex®) is Mix of Botanical Cannabis containing Tetrahydrocannabinol and Cannabidiol Licensed for the treatment of MS Neuropathic Pain in Canada Licensed for the treatment of MS Spasticity in United Kingdom Spain, Germany Denmark & Sweden Italy, Austria & Czech Republic Poland Sativex® Sublingual (under the Tongue) Spray
  14. 14. Prohibited Nabiximols not approved in USA Medicinal Use 29 States Legalised D Nabiximols approved in Canada Recreational & Medical Use Medical Use Medical Use with limited THC content Decriminalised MEDICAL MARIJUANA CANNABINOIDS IN THE CLINIC Despite stare legalisation Cannabis is Illegal based on Federal Law Foreigners caught in possession in USA can be banned for life
  15. 15. Tolerated Illegal but decimalized Illegal but often unenforced Illegal Nabiximols approved in European Union Nabiximols not approved NHS England RECREATIONAL MARIJUANA Medical Cannabis Germany The Netherlands Israel Ireland CANNABINOIDS IN THE CLINIC
  16. 16. Diazepam Baclofen Gabapentin Nabiximols (Sativex) Potassium Ion (K+) expelled (Inside of cell more negative) MECHANISM OF ACTION SPASTICITY BIOLOGY OF CANNABINOIDS Chloride Ion (Cl-) Influx (Inside of cell more negative)
  17. 17. SELECTION OF MARIJUANA >3% THC CONTENT 1970s >3% 2010s >16% >20% CANNABINOIDS IN THE STREET
  18. 18. Price $8-$12/g MEDICAL MARIJUANA OR STONER FOOD SELECTION OF MARIJUANA CANNABINOIDS IN THE STREET
  19. 19. • HERB-MARSH MELLOW PLANT • SYNTHETIC CANNABINOID (NOT CONSISTENT) • SCENT (OPTIONAL) • NOT FOR HUMAN CONSUMPTION LABEL Psychoactive Substances Act 2016. Laws criminalising the production, distribution, sale and supply of psychoactive substances Offenders face up to seven years in prison CANNABINOIDS IN THE STREET
  20. 20. Anandamide (Ki values of 89nM) Tetrahydrocannabinol (Ki values of 10nM) JWH-018 (Ki values of 10nM) CP55, 950 (Ki values of 0.58nM) HU-210 (Ki values are 0.061nM) Anandamide JWH-018 HU-210 THC SPICE CONTENTS (>180 synthetics found) CANNABINOIDS IN THE STREET
  21. 21. LACKS THE CANNABIS SMELL PRISONER APPEAL VULNERABLE PEOPLE HOMELESS PEOPLE PRISONERS VERY POTENT CANNABIS HIGH + OTHERS CAUSES DEATH CHEAP Increase Rate Heart Rate Blood Pressure Fluctuations Chest Pain Headache Vomiting Inability to Speak or move Unconsciousness Extreme Paranoias Memory Loss Seizures CANNABINOIDS IN THE STREET
  22. 22. ANTIDOTE: SOCIETAL-DEAL WITH THE SOCIAL PROBLEM ANTIDOTE: MEDICAL-NONE PROVEN MONITOR & KEEP SAFE MANAGE ADVERSE EVENTS UNTIL EFFECTS WEAR-OFF Smoked cannabis 1-3h Ingested several hours Synthetic cannabinoid hours longer CANNABINOID RECEPTOR INVERSE AGONIST SHOWN IN ANIMALS (CURRENTLY NON-AVAILABLE) Rimonabant/Acomplia CB1 Receptor Antagonist Anti-Obesity Drug Licensed 2006 October 2008 EMEA issued warning Risks outweigh Benefits SEVERE DEPRESSION & SUICIDAL TENDENCIES Licence withdrawn January 2009 CANNABINOIDS IN THE STREET

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