Download Cannabis Lecture - Individual.utoronto.ca

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)
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): 179202.
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.
Kalant, 2001
Mechanisms of Action
Mechanisms of Action (cont’d)
Location of Cannabinoid Receptors
Location
Structure
Function
CB1 receptors
CNS
Periphery
Hippocampus
Memory storage
Cerebellum
Coordination of motor function, posture, balance
Basal ganglia
Movement control
Hypothalamus
Thermal regulation, neuroendocrine release, appetite
Spinal cord
Nociception
Cerebral cortex
Emesis
Lymphoid organs
Cell-mediated and innate immunity
Vascular smooth muscle cells
Control of blood pressure
Duodenum, ileum, myenteric plexus
Control of emesis
Lung smooth muscle cells
Bronchodilation
Eye ciliary body
Intraocular pressure
Lymphoid tissue
Cell-mediated and innate immunity
Peripheral nerve terminals
Peripheral nervous system
Retina
Intraocular pressure
Cerebellar granule cells mRNA
Coordination of motor function
CB2 receptors
Periphery
CNS
Croxford, JL. CNS Drugs 2003; 17(3)
Baker et al, 2003
• 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
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
Relative Affinities of Various Cannabinoids
for CB1 and CB2 Cannabinoid Receptors
Kalant, 2001
Possible Routes of Administration
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
Metabolic Disposition
Metabolic Disposition (cont’d)
Major Metabolic Pathway
Pharmacological Effects
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)
Pharmacological Effects (cont’d)
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
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)
Chronic Effects (cont’d)
• Respiratory System
– ↑ chronic inflammatory chest disease
– precancerous changes
Modern Scientific Research
on Cannabis
Modern Scientific Research
on Cannabis (cont’d)
Actual and Potential Medical Uses
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
Recent Clinical Trials of Cannabinoids
for the Treatment of CNS Disorders
Disorder
Multiple Sclerosis
Target Symptoms
Therapeutic
Cannabinoid
Clinical Outcome
Spasticity
Oral THC, CBD
In progress
Neurogenic pain
Sublingual THC, CBD
Phase II trial in progress
Bladder dysfunction Sublingual THC, CBD
Phase II trial in progress
Dystonia
Nabilone
No effect
Dyskinesia
Nabilone
 Dyskinesia
Tremor
9-THC
No effect
Cancer
Pain
Sublingual THC, CBD
Phase III trial in
progress
Postoperative pain
Pain
IM levonantradol
 pain, but less effective
than existing therapies
Parkinsons’s
disease
CBD = cannabidiol
THC = tetrahydrocannabinol
Croxford, JL. CNS Drugs 2003; 17(3)
Recent Clinical Trials of Cannabinoids for
the Treatment of CNS Disorders (cont’d)
Disorder
Target Symptoms
Therapeutic
Cannabinoid
Clinical Outcome
Spinal cord injury
Pain
Sublingual THC,
CBD
Phase II trial in progress
GI tract pain
Pain
THC
 Morphine requirement
Traumatic Brain
Injury / Stroke
Neurodegeneration
IV dexanabinol
(HU-211)
Intracranial pressure,
 mortality, phase III trial
in progress
Neurodegeneration
CBD
In progress
Appetite loss, nausea
Smoked cannabis In progress
Appetite loss, nausea
Dronabinol
HIV wasting
syndrome
Tourette’s syndrome
Behavioural disorders THC
 appetite,  nausea
undetermined
Croxford, JL. CNS Drugs 2003; 17(3)
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
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
Relief of Spasticity
(e.g., Multiple Sclerosis)
Relief of Spasticity
(e.g., Multiple Sclerosis)
Glaucoma
Glaucoma (cont’d)
Potential Adverse Effects of Cannabinoid Therapy
Adverse Effects
Description
Acute effects
Euphoria
Decreased anxiety, alertness, tension, depression
Sedation
CNS depression, drowsiness
Perception
Temporal and spatial distortion
Motor function
Ataxia, incoordination, reduced reaction time
Psychomotor function
Impaired hand-eye coordination
Cognition
Deficit in short-term memory, mental confusion
Psychosis
Anxiety, confusion, disorientation, may aggravate schizophrenia
Tolerance
Reduced acute effects of cannabis use
Immunosuppression
No evidence for long-term immunosuppression
Chronic effects
Respiratory system
Bronchitis, emphysema as with normal cigarette smoking
Cardiovascular system
Tachycardia, postural hypotension,  body temperature, may aggravate existing
heart disease
Reproductive system
Decreased sperm counts
Croxford, JL. CNS Drugs 2003; 17(3)
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
Problems in Design of Clinical Trials
Problems in Design of Clinical Trials
Problems in Design of Clinical Trials
Problems in Design of Clinical Trials
Problems in Design of Clinical Trials
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)
Considerations in Use of Crude Cannabis
versus Pure Cannabinoids (cont’d)
Historical Comparisons between
Cannabinoids and Opioids