Therapeutic Uses of Cannabis B. Brands, Ph.D. Centre for Addiction and Mental Health Clinical Research Department Department of Pharmacology University of Toronto (Presented by Wende Wood, B.A., B.S.P., B.C.P.P. Drug Information and Drug Use Evaluation Pharmacist)
Therapeutic Uses of Cannabis B. Brands, Ph.D. Centre for Addiction and Mental Health Clinical Research Department Department of Pharmacology University.
Dec 23, 2015
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- Therapeutic Uses of Cannabis B. Brands, Ph.D. Centre for Addiction and Mental Health Clinical Research Department Department of Pharmacology University of Toronto (Presented by Wende Wood, B.A., B.S.P., B.C.P.P. Drug Information and Drug Use Evaluation Pharmacist)
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- Excerpted from: Kalant, H. (2001) Medicinal use of cannabis: History and current status. Pain Res. Manage 6(2): 80-91. Other Sources: Baker et al (2003) The therapeutic potential of cannabis. The Lancet. Neurology 2: 291-298. Croxford, J.L. (2003) Therapeutic potential of cannabinoids in CNS disease. CNS Drugs 17(3): 179- 202. Joy, J.E. et al (1999) Marijuana and medicine: Assessing the science base. Washington, D.C., National Academy Press. Additional Reading:Bagshaw, S.M. (2002) Medical efficacy of cannabinoids and marijuana: A comprehensive review of the literature. Journal of Palliative Care 18(2) 111-122. Iverson, L. (2003) Cannabis and the Brain. Brain 126: 1252-1270.
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- Kalant, 2001
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- Mechanisms of Action
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- Mechanisms of Action (contd)
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- Location of Cannabinoid Receptors LocationStructureFunction CB 1 receptors CNSHippocampusMemory storage CerebellumCoordination of motor function, posture, balance Basal gangliaMovement control HypothalamusThermal regulation, neuroendocrine release, appetite Spinal cordNociception Cerebral cortexEmesis PeripheryLymphoid organsCell-mediated and innate immunity Vascular smooth muscle cellsControl of blood pressure Duodenum, ileum, myenteric plexusControl of emesis Lung smooth muscle cellsBronchodilation Eye ciliary bodyIntraocular pressure CB 2 receptors PeripheryLymphoid tissueCell-mediated and innate immunity Peripheral nerve terminalsPeripheral nervous system RetinaIntraocular pressure CNSCerebellar granule cells mRNACoordination of motor function Croxford, JL. CNS Drugs 2003; 17(3)
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- Baker et al, 2003
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- receptors are linked to G i protein decrease adenylyl cyclase activity prevent activation of various Ca 2+ channels and activate K + influx major effect - decreased cell excitability probably modify responses to various neurotransmitters, and NT release
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- Diagram of Neuron with Synapse Individual nerve cells, or neurons, both send and receive cellular signals to and from neighbouring neurons, but for the purposes of the previous diagram, only one activity is indicated for each cell. Neurotransmitter molecules are released from the neuron terminal and move across the gap between the sending and receiving neurons. A signal is transmitted to the receiving neuron when the neurotransmitters have bound to the receptor on its surface. From: Marijuana and Medicine: Assessing the Science Base, IOM 1999
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- Relative Affinities of Various Cannabinoids for CB1 and CB2 Cannabinoid Receptors Kalant, 2001
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- Possible Routes of Administration
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- Possible Routes of Administration (contd) IV- very low water solubility, requires special formulation - rapid onset of action - dosage limitations short duration of effect Smoking - rapid absorption (like IV) - bioavailability 18-50% - high variability due to smoking techniques Topical - very limited applicability
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- Metabolic Disposition
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- Metabolic Disposition (contd)
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- Major Metabolic Pathway
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- Pharmacological Effects
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- Pharmacological Effects (contd) Acute Effects Pain perception (exerted at CB 1 receptor) Antinauseant and antiemetic effects, appetite (CB 1 receptors) Anticonvulsant effects (not via CB 1 receptors)
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- Pharmacological Effects (contd)
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- Respiratory Bronchodilation airway resistance (acute) Bronchial irritation particulate fraction of cannabis smoke (chronic) Cannabis smoke similar to tobacco smoke Eye IOP at doses that produce CNS effects Immune System Effects unclear
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- Chronic Effects CNS cognitive changes include poor memory, vagueness of thought, decreased verbal fluency, learning deficits daily high doses can cause chronic intoxication syndrome (apathy), confusion, depression, paranoia cannabis dependence (DSM-IV criteria)
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- Chronic Effects (contd) Respiratory System chronic inflammatory chest disease precancerous changes
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- Modern Scientific Research on Cannabis
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- Modern Scientific Research on Cannabis (contd)
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- Actual and Potential Medical Uses
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- Actual and Potential Medical Uses (contd) Modern western medicine: Accepted uses antinauseant, antiemetic appetite stimulant cancer chemotherapy, AIDS Possible uses worth study: analgesia antispasticity (e.g. multiple sclerosis) immunosuppressant glaucoma anticonvulsant, mainly cannabidiol, not THC
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- Recent Clinical Trials of Cannabinoids for the Treatment of CNS Disorders DisorderTarget SymptomsTherapeutic Cannabinoid Clinical Outcome Multiple SclerosisSpasticityOral THC, CBDIn progress Neurogenic painSublingual THC, CBDPhase II trial in progress Bladder dysfunctionSublingual THC, CBDPhase II trial in progress Parkinsonss disease DystoniaNabiloneNo effect DyskinesiaNabilone Dyskinesia Tremor 9-THC No effect CancerPainSublingual THC, CBDPhase III trial in progress Postoperative painPainIM levonantradol pain, but less effective than existing therapies Croxford, JL. CNS Drugs 2003; 17(3) CBD = cannabidiol THC = tetrahydrocannabinol
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- Recent Clinical Trials of Cannabinoids for the Treatment of CNS Disorders (contd) DisorderTarget SymptomsTherapeutic Cannabinoid Clinical Outcome Spinal cord injuryPainSublingual THC, CBD Phase II trial in progress GI tract painPainTHC Morphine requirement Traumatic Brain Injury / Stroke NeurodegenerationIV dexanabinol (HU-211) Intracranial pressure, mortality, phase III trial in progress NeurodegenerationCBDIn progress HIV wasting syndrome Appetite loss, nauseaSmoked cannabisIn progress Appetite loss, nauseaDronabinol appetite, nausea Tourettes syndromeBehavioural disordersTHCundetermined Croxford, JL. CNS Drugs 2003; 17(3)
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- Analgesia CB 1 -selective agonists reduce pain receptors in periaqueductal gray mainly (direct local injection effective) separate from opioid analgesia mechanism naloxone blocks morphine analgesia but not THC analgesia CB 1 blocker (SR 141716A) blocks THC but not morphine analgesia but THC and morphine augment each others effects - possibility of combined use
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- Analgesia (contd) both oral THC and smoked marijuana work onset of action faster with smoking for chronic pain, speed not necessary new water-soluble esters of THC-acid analogs analgesic and anti-inflammatory action no psychoactivity, no gastric irritation possible replacement for NSAIDs? migraine only anecdotal evidence no controlled comparison of oral vs smoked
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- Relief of Spasticity (e.g., Multiple Sclerosis)
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- Glaucoma
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- Glaucoma (contd)
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- Potential Adverse Effects of Cannabinoid Therapy Adverse EffectsDescription Acute effects EuphoriaDecreased anxiety, alertness, tension, depression SedationCNS depression, drowsiness PerceptionTemporal and spatial distortion Motor functionAtaxia, incoordination, reduced reaction time Psychomotor functionImpaired hand-eye coordination CognitionDeficit in short-term memory, mental confusion PsychosisAnxiety, confusion, disorientation, may aggravate schizophrenia ToleranceReduced acute effects of cannabis use ImmunosuppressionNo evidence for long-term immunosuppression Chronic effects Respiratory systemBronchitis, emphysema as with normal cigarette smoking Cardiovascular system Tachycardia, postural hypotension, body temperature, may aggravate existing heart disease Reproductive systemDecreased sperm counts Croxford, JL. CNS Drugs 2003; 17(3)
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- Problems in Design of Clinical Trials Almost no data on pharmacokinetics during chronic treatment long t means risk of accumulation need to monitor residual levels regularly Distribution between plasma and tissues may invalidate ordinary methods for measurement of bioavailability
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- Problems in Design of Clinical Trials
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- Considerations in Use of Crude Cannabis versus Pure Cannabinoids adequate control of dosage smoking more variable unless tightly controlled available routes of administration cannabis: smoked or ingested pure THC or cannabinoids: oral, rectal, aerosol inhalation, topical selectivity of therapeutic action better promise with synthetic derivatives (receptor selectivity)
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- Considerations in Use of Crude Cannabis versus Pure Cannabinoids (contd)
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- Historical Comparisons between Cannabinoids and Opioids
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