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 ofcannabinoids 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 ReceptorsLocation 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 Cannabinoid

Clinical Outcome

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 disease

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

Croxford, JL. CNS Drugs 2003; 17(3)CBD = cannabidiol

THC = tetrahydrocannabinol

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

HIV wasting syndrome

Appetite loss, nausea Smoked cannabis In progress

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 TherapyAdverse 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