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): 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.
Kalant, 2001
Mechanisms of Action
Mechanisms of Action (cont’d)
 Location of Cannabinoid Receptors
Location Structure Function
CB1 receptors
CNS 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
Periphery 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
CB2 receptors
Periphery Lymphoid tissue Cell-mediated and innate immunity
Peripheral nerve terminals Peripheral nervous system
Retina Intraocular pressure
CNS Cerebellar granule cells mRNA Coordination of motor function

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 Target Symptoms Therapeutic Clinical Outcome
Cannabinoid
Multiple Sclerosis 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
Parkinsons’s Dystonia Nabilone No effect
disease
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

CBD = cannabidiol
Croxford, JL. CNS Drugs 2003; 17(3)
THC = tetrahydrocannabinol
Recent Clinical Trials of Cannabinoids for
the Treatment of CNS Disorders (cont’d)
Disorder Target Symptoms Therapeutic Clinical Outcome
Cannabinoid
Spinal cord injury Pain Sublingual THC, Phase II trial in progress
CBD
GI tract pain Pain THC  Morphine requirement

Traumatic Brain Neurodegeneration IV dexanabinol Intracranial pressure,

Injury / Stroke (HU-211)  mortality, phase III trial
in progress
Neurodegeneration CBD In progress

HIV wasting Appetite loss, nausea Smoked cannabis In progress

syndrome
Appetite loss, nausea Dronabinol  appetite,  nausea
Tourette’s syndrome Behavioural disorders THC 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