Pharmacology of Cannabis

Emily Brown, Puranjay Mahajan, and Caylie Poirier24 November 2015

PHM142 Fall 2015Instructor: Dr. Jeffrey Henderson

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Introduction

• Early human civilizations

• Cannabinoids: Δ9-THC, Δ8-THC, cannabinol, and cannabidiol

• Lipophilic, fused tricyclic structure

• Many preparations

Δ9-THC

Huffingtonpost (2013)

Ashton CH.

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Overview of Pharmacokinetics

• THC reaches the brain within minutes• Distribution dependent on blood flow to tissue• Accumulation in fat

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Pharmacodynamics of Cannabis

• Mechanism of action of cannabinoids have been associated with cannabinoid receptors such as CB1 and CB2.

• CB1 receptors are found in the neuron terminals of the basal ganglia, cerebellum, hippocampus, neocortex, hypothalamus and limbic cortex.

• CB1 neurons as result affect motor activity and coordination, memory, thinking and appetite and sedation.

• CB2 receptors are found on immune cells and trigger inflammatory and immunosuppressive activity.

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• THC is a partial agonist that binds to CB1 receptors on pre-synaptic nerve terminals.

• This activates G proteins which activate/inhibit a number of pathways.

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• The G proteins directly inhibit N and P/Q type voltage dependent calcium channels and sodium channels.

• G proteins indirectly inhibit A-type calcium channels by inhibiting adenylate cyclase which reduces cAMP and protein kinase activity.

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• G protein activation activates inwardly rectifying potassium channels and MAP kinase signaling pathway.

• By affecting all these calcium and potassium channels, release of the neurotransmitter GABA is inhibited.

• GABA is an inhibitory neurotransmitter and inhibition of GABA results in release of dopamine which is what causes that feeling of euphoria, relaxation, and amplified auditory and visual perceptions.

8CNSforum (2014)

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Therapeutic Uses of Cannabinoids• Antiemetic• Antiepileptic• Therapy for insomnia • Glaucoma treatment• Appetite stimulant (AIDS)• Analgesic/Antinociceptive• Muscle relaxant • Treatment for Alzheimer’s **

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Alzheimer’s Disease and THC

• Neurodegenerative disorder• Plaques caused by β-amyloid aggregation• Tangles caused by tau hyper-phosphorylation

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• Eubanks et al.• AchE promotes β-amyloid aggregation• Propidium is a PAS ligand • THC competitively inhibits AchE• Binds to AchE peripheral anionic binding site and

decreases β-amyloid aggregation

Eubanks et al.

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Some Medicinal CannabinoidsNabilone- More potent analog of THC- Antiemetic in cancer chemotherapy- Pain relief- Reduce agitation and aggression in Alzheimer’s- Side effects: drowsiness, dysphoria, dry mouth, ataxiaSativex (nabiximols)- Multiple sclerosis treatment

- Spasticity - Neuropathic pain

- Cancer pain

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Recreational Use• Most commonly used and abused illicit substance

• Euphoriant effect or “high”

• Dysphoric reactions

• Hallucinations

• Potential dependence and behavioural disturbances

• Increased risk of psychotic disorders

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Challenges

• Legality • Variable effect of medical cannabis

– Unknown safety and tolerability– Method of delivery– Patient individuality

• Surveillance of patients• Study subjects

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Summary• Δ9-THC is the major cannabinoid and has the greatest pharmacologic effect

• Many different preparations

• CB1 receptors are located in the central nervous system

• CB2 receptors are located in the immune cells

• Many therapeutic uses: Nabilone and Sativex

• More research needed for comprehensive understanding

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Summary

CNSforum (2014)

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References1. Ashton CH. Pharmacology and effects of cannabis: a brief review. Brit J Psychiat 2001;

178: 101-106.2. Borgelt LM, Franson KL, Nussbaum AM, Wang GS. The Pharmacologic and Clinical Effects

of Medical Cannabis. Pharmacotherapy 2013; 33(2): 195-209.3. Eubanks LM, Rogers CJ, Beuscher AE, Koob GF, Olson AJ, Dickerson TJ, Janda KD. A

Molecular Link Between the Active Component of Marijuana and Alzheimer’s Disease Pathology. Mol Pharm 2006; 3(6): 773-777.

4. Hirst RA, Lambert DG, Notcutt WG. Pharmacology and potential therapeutic uses of cannabis. Brit J Anaesth 1998; 81: 77-84.

5. Liu CS, Chau SA, Ruthirakuhan M, Lanctôt KL, and Herrmann N. Cannabinoids for the Treatment of Agitation and Aggression in Alzheimer’s Disease. CNS Drugs 2015; 29(8): 615-23. Web.

6. Laaris N, Good CH, Lupica CR. Delta9-tetrahydrocannabinol is a full agonist at CB1 receptors on GABA neuron axon terminals in the hippocampus. Neuropharmacology 2010; (1-2): 121-7

7. https://www.cnsforum.com/educationalresources/imagebank/substance_abuse/moa_cannab

8. http://www.huffingtonpost.com/2013/07/23/germany-marijuana-plants-protest_n_3639468.html