Therapeutic Uses of Cannabis

1. 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)

2. 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.

3. Kalant, 2001

5. Mechanisms of Action

6. Mechanisms of Action (cont’d)

7. Location of Cannabinoid Receptors Croxford, JL. CNS Drugs 2003; 17(3)

8. Baker et al, 2003

9. receptors are linked to Gi protein • decrease adenylyl cyclase activity • prevent activation of various Ca2+ channels and activate K+ influx • major effect - decreased cell excitability • probably modify responses to various neurotransmitters, and  NT release

10. 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

11. Relative Affinities of Various Cannabinoids for CB1 and CB2 Cannabinoid Receptors Kalant, 2001

12. Possible Routes of Administration

13. Possible Routes of Administration (cont’d) • 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

14. Metabolic Disposition

15. Metabolic Disposition (cont’d)

16. Major Metabolic Pathway

17. Pharmacological Effects

18. Pharmacological Effects (cont’d) Acute Effects • Pain perception ↓ (exerted at CB1 receptor) • Antinauseant and antiemetic effects, ↑ appetite (CB1 receptors) • Anticonvulsant effects (not via CB1 receptors)

19. Pharmacological Effects (cont’d)

20. Pharmacological Effects (cont’d) 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

21. 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)

22. Chronic Effects (cont’d) • Respiratory System • ↑ chronic inflammatory chest disease • precancerous changes

23. Modern Scientific Research on Cannabis

24. Modern Scientific Research on Cannabis (cont’d)

25. Actual and Potential Medical Uses

26. Actual and Potential Medical Uses (cont’d) • 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

27. Recent Clinical Trials of Cannabinoids for the Treatment of CNS Disorders CBD = cannabidiol THC = tetrahydrocannabinol Croxford, JL. CNS Drugs 2003; 17(3)

28. Recent Clinical Trials of Cannabinoids for the Treatment of CNS Disorders (cont’d) Croxford, JL. CNS Drugs 2003; 17(3)

29. Analgesia • CB1-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 • CB1 blocker (SR 141716A) blocks THC but not morphine analgesia • but THC and morphine augment each other’s effects - possibility of combined use

30. Analgesia (cont’d) • 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

31. Relief of Spasticity (e.g., Multiple Sclerosis)

32. Relief of Spasticity (e.g., Multiple Sclerosis)

33. Glaucoma

34. Glaucoma (cont’d)

35. Potential Adverse Effects of Cannabinoid Therapy Croxford, JL. CNS Drugs 2003; 17(3)

36. Problems in Design of Clinical Trials • Almost no data on pharmacokinetics during chronic treatment – long t½ means risk of accumulation – need to monitor residual levels regularly • Distribution between plasma and tissues may invalidate ordinary methods for measurement of bioavailability

37. Problems in Design of Clinical Trials

38. Problems in Design of Clinical Trials

39. Problems in Design of Clinical Trials

40. Problems in Design of Clinical Trials

41. Problems in Design of Clinical Trials

42. 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)

43. Considerations in Use of Crude Cannabis versus Pure Cannabinoids (cont’d)

44. Historical Comparisons between Cannabinoids and Opioids