1. Nabilone in C.I.N.V. August 2007
Increasingly, cannabinoids (CBs) are being used to treat a variety of diseases and symptoms. However, the mechanisms by which these agents exert their multiple therapeutic effects have only been elucidated recently. Today’s presentation describes a novel term, Omnineuromodulation™, that describes the scientific platform and mechanism of action by which CB agonists assert their therapeutic effects in the treatment of chemotherapy-induced nausea and vomiting (CINV), cachexia, and neuropathic pain (NP).

2. Introduction
Present a scientific validation for cannabinoids (CBs) asserting their therapeutic effects through Omnineuromodulation
CBs activate CB1 endocannabinoid receptors, which are omnipresent throughout the Central Nervous System (CNS)
Action on these receptors modulates neuronal signaling
Review evidence showing how omnineuromodulation underlies the therapeutic role of CBs in the management of Chemotherapy-Induced Nausea and Vomiting (CINV)

3. The Ubiquitous CB1
Endogenous CBs are a major class of neuromodulators, acting through receptors, CB1 and CB2
CB1 receptors are primarily located on CNS neurons
Levels exceed those of nearly all neurotransmitter receptors
Exogenous CBs exert their effects by driving this innate system, often mimicking and enhancing its natural functions
Activating an Innate Neuromodulatory System
The last 15 years have brought the discovery of an endogenous, or endocannabinoid, system consisting of two cannabinoid receptors—CB1 and CB2—and the two main ligands that act on these receptors, anandamide and 2-arachidonyl-glycerol (2-AG).{Croxford, 2003} CB1 receptors are primarily located on neurons of the central and peripheral nervous system, while CB2 receptors are mainly located on immune cells in the periphery.{Croxford, 2003} CB1 receptors are present in high quantities in the CNS, exceeding the levels of nearly all neurotransmitter receptors.{Martin and Wiley, 2004} Cannabinoid receptors are among the most ubiquitous neurotransmitter elements in the brain, as they exist in virtually every brain region and on many different types of neurons.{Howlett et al, 2004} They have been shown to inhibit neuronal signaling involving various neurotransmitters.{Schlicker and Kathmann, 2001} In the brain regions where CB1 receptors are especially concentrated, the normal biology and behavior associated with these brain areas are consistent with the physiological and behavioral effects produced by cannabinoids.{Martin and Wiley, 2004}
Given the omnipresent distribution and highly concentrated levels of the CB1 receptors in the nervous system, endogenous cannabinoids are considered a major class of neuromodulators.{Martin and Wiley, 2004} Exogenous cannabinoids exert their effects by driving this innate system, often mimicking and enhancing its natural functions. One example of an exogenous cannabinoid is ∆9-THC (∆9-tetrahydrocannabinol), the major psychoactive component of cannabis.{Croxford, 2003} Nabilone (nabilone) is a synthetic analog of ∆9-THC.{Nabilone (Nabilone) Prescribing Information; Ward and Holmes, 1985} Classical cannabinoids such as ∆9-THC and nabilone generally signal through both CB1 and CB2 receptors. Their therapeutic effects can be explained primarily by agonist action on these receptors {Croxford, 2003} in critical brain regions that mediate nausea/emesis, appetite, and neuropathic pain.{Martin and Wiley, 2004} This neuromodulatory effect, coupled with the omnipresent central distribution of the CB1 receptors, has led to the proposed term, “Omnineuromodulator,”TM to describe the action of exogenous cannabinoids at the innate cannabinoid receptors.
References
Nabilone (Nabilone) Prescribing Information.
Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):
Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47 Suppl 1:
Kalant H. Medicinal use of cannabis: History and current status. Pain Res Manage Vol 6 No 2.
Martin BR, Wiley JL. Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain. J Support Oncol Jul-Aug;2(4):305-14; discussion
Schlicker E, Kathmann M. Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci Nov;22(11):
Ward A, Holmes B. Nabilone. A preliminary review of its pharmacological properties and therapeutic use. Drugs Aug;30(2):

4. The Ubiquitous CB1
The omnipresent central distribution of CB1, has led to the term, Omnineuromodulator, to describe CB action
Therapeutic effects are primarily due to agonist action in brain regions that mediate nausea/vomiting, appetite, and neuropathic pain
Activating an Innate Neuromodulatory System
The last 15 years have brought the discovery of an endogenous, or endocannabinoid, system consisting of two cannabinoid receptors—CB1 and CB2—and the two main ligands that act on these receptors, anandamide and 2-arachidonyl-glycerol (2-AG).{Croxford, 2003} CB1 receptors are primarily located on neurons of the central and peripheral nervous system, while CB2 receptors are mainly located on immune cells in the periphery.{Croxford, 2003} CB1 receptors are present in high quantities in the CNS, exceeding the levels of nearly all neurotransmitter receptors.{Martin and Wiley, 2004} Cannabinoid receptors are among the most ubiquitous neurotransmitter elements in the brain, as they exist in virtually every brain region and on many different types of neurons.{Howlett et al, 2004} They have been shown to inhibit neuronal signaling involving various neurotransmitters.{Schlicker and Kathmann, 2001} In the brain regions where CB1 receptors are especially concentrated, the normal biology and behavior associated with these brain areas are consistent with the physiological and behavioral effects produced by cannabinoids.{Martin and Wiley, 2004}
Given the omnipresent distribution and highly concentrated levels of the CB1 receptors in the nervous system, endogenous cannabinoids are considered a major class of neuromodulators.{Martin and Wiley, 2004} Exogenous cannabinoids exert their effects by driving this innate system, often mimicking and enhancing its natural functions. One example of an exogenous cannabinoid is ∆9-THC (∆9-tetrahydrocannabinol), the major psychoactive component of cannabis.{Croxford, 2003} Nabilone (nabilone) is a synthetic analog of ∆9-THC.{Nabilone (Nabilone) Prescribing Information; Ward and Holmes, 1985} Classical cannabinoids such as ∆9-THC and nabilone generally signal through both CB1 and CB2 receptors. Their therapeutic effects can be explained primarily by agonist action on these receptors {Croxford, 2003} in critical brain regions that mediate nausea/emesis, appetite, and neuropathic pain.{Martin and Wiley, 2004} This neuromodulatory effect, coupled with the omnipresent central distribution of the CB1 receptors, has led to the proposed term, “Omnineuromodulator,”TM to describe the action of exogenous cannabinoids at the innate cannabinoid receptors.
References
Nabilone (Nabilone) Prescribing Information.
Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):
Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47 Suppl 1:
Kalant H. Medicinal use of cannabis: History and current status. Pain Res Manage Vol 6 No 2.
Martin BR, Wiley JL. Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain. J Support Oncol Jul-Aug;2(4):305-14; discussion
Schlicker E, Kathmann M. Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci Nov;22(11):
Ward A, Holmes B. Nabilone. A preliminary review of its pharmacological properties and therapeutic use. Drugs Aug;30(2):

5. Omnineuromodulation
Nabilone acts on presynaptic CB1 receptors, similar to endocannabinoids
Inhibits the release of excitatory (e.g., glutamate) and inhibitory (e.g., GABA) neurotransmitters
The primary effect on neuronal signaling appears to be inhibitory, but network effects may be complex and hence modulatory in nature
Endogenous CB1 ligands act “backwards” from classical neurotransmitters by serving as retrograde synaptic messengers
Central Omnineuromodulator Action
Exogenous cannabinoid omnimodulators, such as Nabilone (nabilone), exert their effects via agonist action on the presynaptic CB1 receptors, in a manner similar to endocannabinoids.{Croxford, 2003} Evidence suggests that such activation of presynaptic CB1 receptors can lead to inhibition of the evoked release of a number of excitatory (e.g., glutamate) and inhibitory (e.g., GABA) neurotransmitters, both in the central and peripheral nervous systems.{Howlett et al, 2002; Schlicker and Kathmann, 2001} Thus, cannabinoids have been shown to inhibit GABA release in the basal ganglia and glutamate release in the cerebellum.{Freund et al, 2003} A unifying theme is the widespread occurrence of presynaptic CB1 receptors on local GABAergic interneurons.{Freund et al, 2003}
Although the primary effect of CB1 receptor agonists on neuronal signaling appears to be inhibitory, their network effects may be complex and hence modulatory in nature.{Howlett et al, 2002; Martin and Wiley, 2004} An initial inhibitory effect may trigger enhanced neurotransmitter release downstream, resulting in a net activating effect.{Howlett et al, 2002} For example, decreasing the release of the inhibitory neurotransmitter GABA can “disinhibit,” or activate, neurons with which the GABA cells are communicating. Another example of a downstream effect produced by CB1 receptor agonists is the stimulation of dopamine release in a “reward center” (the nucleus accumbens). In this case, it is likely that the cannabinoid receptor-mediated disinhibition of dopamine release stems from an inhibition of glutamate release from extrinsic glutamatergic, rather than GABAergic, fibers.{Howlett et al, 2002; Schlicker and Kathmann, 2001}
Endogenous Retrograde, or “Backward,” Signaling and Exogenous Cannabinoids
In addition to this seemingly contradictory inhibitory/excitatory effect, evidence suggests that endogenous CB1 ligands act “backwards” from classical neurotransmitters by serving as retrograde synaptic messengers.{Diana and Marty, 2004} Endocannabinoid signaling is a multi-step process, while exogenous cannabinoids work more directly (step 5): [SEE NEXT PAGES IN SHOW]
1. Neurotransmitter released from vesicles within the presynaptic neuron activates the postsynaptic neuron
2. Activation of the postsynaptic neuron leads to the biosynthesis and nonvesicular release of an endocannabinoid, likely via a calcium mediated process {Howlett et al, 2002; Piomelli, 2003; Howlett et al, 2004}
3. The endogenous CB1 ligand diffuses back to and binds to the presynaptic CB1 receptor {Piomelli, 2003}
4. The CB1 receptor activates a G protein which can lead to a number of presynaptic downstream events (e.g., effects on ion currents) that result in the inhibition of neurotransmitter release {Diana and Marty, 2004; Freund et al, 2003}
5. Exogenous cannabinoids circumvent this multi-step process by directly activating CB1 receptors and stimulating the endogenous cannabinoid system,{Croxford, 2003} mimicking or enhancing its natural functions
Definitions of ligands:
molecules, either synthetic or of natural origin, that are able to specifically bind certain proteins. In the case of natural ligands, such as hormones, the proteins they bind are called receptors.
are any compounds that bind to a receptor.
in chemistry, a ligand is an atom, ion or functional group that is bonded to one or more central atoms or ions, usually metals generally through co-ordinate covalent bond. An array of such ligands around a centre is termed a complex.
References
Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):
Diana MA, Marty A. Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). Br J Pharmacol May;142(1):9-19. Epub 2004 Apr 20.
Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev Jul;83(3):
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev Jun;54(2):16
Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47 Suppl 1:
Martin BR, Wiley JL. Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain. J Support Oncol Jul-Aug;2(4):305-14; discussion
Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci Nov;4(11):
Schlicker E, Kathmann M. Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci Nov;22(11):

6. A Sequential Overview of Omnineuromodulation

7. Neurotransmitter (NT) released from vesicles within the presynaptic neuron activates the postsynaptic neuron
Endocannabinoid signaling is a multi-step process, while exogenous cannabinoids work more directly (step 5):
1. Neurotransmitter released from vesicles within the presynaptic neuron activates the postsynaptic neuron
2. Activation of the postsynaptic neuron leads to the biosynthesis and nonvesicular release of an endocannabinoid, likely via a calcium mediated process {Howlett et al, 2002; Piomelli, 2003; Howlett et al, 2004}
3. The endogenous CB1 ligand diffuses back to and binds to the presynaptic CB1 receptor {Piomelli, 2003}
4. The CB1 receptor activates a G protein which can lead to a number of presynaptic downstream events (e.g., effects on ion currents) that result in the inhibition of neurotransmitter release {Diana and Marty, 2004; Freund et al, 2003}
5. Exogenous cannabinoids circumvent this multi-step process by directly activating CB1 receptors and stimulating the endogenous cannabinoid system,{Croxford, 2003} mimicking or enhancing its natural functions
References
Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):
Diana MA, Marty A. Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). Br J Pharmacol May;142(1):9-19. Epub 2004 Apr 20.
Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev Jul;83(3):
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev Jun;54(2):16
Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47 Suppl 1:
Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci Nov;4(11):

8. Activation of the postsynaptic neuron leads to the biosynthesis and nonvesicular release of an endocannabinoid, likely via a calcium mediated process
Endocannabinoid signaling is a multi-step process, while exogenous cannabinoids work more directly (step 5):
1. Neurotransmitter released from vesicles within the presynaptic neuron activates the postsynaptic neuron
2. Activation of the postsynaptic neuron leads to the biosynthesis and nonvesicular release of an endocannabinoid, likely via a calcium mediated process {Howlett et al, 2002; Piomelli, 2003; Howlett et al, 2004}
3. The endogenous CB1 ligand diffuses back to and binds to the presynaptic CB1 receptor {Piomelli, 2003}
4. The CB1 receptor activates a G protein which can lead to a number of presynaptic downstream events (e.g., effects on ion currents) that result in the inhibition of neurotransmitter release {Diana and Marty, 2004; Freund et al, 2003}
5. Exogenous cannabinoids circumvent this multi-step process by directly activating CB1 receptors and stimulating the endogenous cannabinoid system,{Croxford, 2003} mimicking or enhancing its natural functions
References
Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):
Diana MA, Marty A. Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). Br J Pharmacol May;142(1):9-19. Epub 2004 Apr 20.
Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev Jul;83(3):
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev Jun;54(2):16
Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47 Suppl 1:
Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci Nov;4(11):

9. The endocannabinoid diffuses back to and binds to the presynaptic CB1 receptor
Endocannabinoid signaling is a multi-step process, while exogenous cannabinoids work more directly (step 5):
1. Neurotransmitter released from vesicles within the presynaptic neuron activates the postsynaptic neuron
2. Activation of the postsynaptic neuron leads to the biosynthesis and nonvesicular release of an endocannabinoid, likely via a calcium mediated process {Howlett et al, 2002; Piomelli, 2003; Howlett et al, 2004}
3. The endocannabinoid diffuses back to and binds to the presynaptic CB1 receptor {Piomelli, 2003}
4. The CB1 receptor activates a G protein which can lead to a number of presynaptic downstream events (e.g., effects on ion currents) that result in the inhibition of neurotransmitter release {Diana and Marty, 2004; Freund et al, 2003}
5. Exogenous cannabinoids circumvent this multi-step process by directly activating CB1 receptors and stimulating the endogenous cannabinoid system,{Croxford, 2003} mimicking or enhancing its natural functions
References
Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):
Diana MA, Marty A. Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). Br J Pharmacol May;142(1):9-19. Epub 2004 Apr 20.
Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev Jul;83(3):
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev Jun;54(2):16
Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47 Suppl 1:
Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci Nov;4(11):

10. The CB1 receptor activates a G protein which can lead to a number of presynaptic downstream events (e.g., effects on ion currents) that result in the inhibition of neurotransmitter release
Endocannabinoid signaling is a multi-step process, while exogenous cannabinoids work more directly (step 5):
1. Neurotransmitter released from vesicles within the presynaptic neuron activates the postsynaptic neuron
2. Activation of the postsynaptic neuron leads to the biosynthesis and nonvesicular release of an endocannabinoid, likely via a calcium mediated process {Howlett et al, 2002; Piomelli, 2003; Howlett et al, 2004}
3. The endocannabinoid diffuses back to and binds to the presynaptic CB1 receptor {Piomelli, 2003}
4. The CB1 receptor activates a G protein which can lead to a number of presynaptic downstream events (e.g., effects on ion currents) that result in the inhibition of neurotransmitter release {Diana and Marty, 2004; Freund et al, 2003}
5. Exogenous cannabinoids circumvent this multi-step process by directly activating CB1 receptors and stimulating the endogenous cannabinoid system,{Croxford, 2003} mimicking or enhancing its natural functions
References
Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):
Diana MA, Marty A. Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). Br J Pharmacol May;142(1):9-19. Epub 2004 Apr 20.
Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev Jul;83(3):
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev Jun;54(2):16
Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47 Suppl 1:
Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci Nov;4(11):

11. CB agents, acting as Omnineuromodulators, circumvent this multi-step process by directly activating CB1 receptors to stimulate the endogenous CB system, enhancing its function
Endocannabinoid signaling is a multi-step process, while exogenous cannabinoids work more directly (step 5):
1. Neurotransmitter released from vesicles within the presynaptic neuron activates the postsynaptic neuron
2. Activation of the postsynaptic neuron leads to the biosynthesis and nonvesicular release of an endocannabinoid, likely via a calcium mediated process {Howlett et al, 2002; Piomelli, 2003; Howlett et al, 2004}
3. The endocannabinoid diffuses back to and binds to the presynaptic CB1 receptor {Piomelli, 2003}
4. The CB1 receptor activates a G protein which can lead to a number of presynaptic downstream events (e.g., effects on ion currents) that result in the inhibition of neurotransmitter release {Diana and Marty, 2004; Freund et al, 2003}
5. Exogenous cannabinoids circumvent this multi-step process by directly activating CB1 receptors and stimulating the endogenous cannabinoid system,{Croxford, 2003} mimicking or enhancing its natural functions
References
Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):
Diana MA, Marty A. Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). Br J Pharmacol May;142(1):9-19. Epub 2004 Apr 20.
Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev Jul;83(3):
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev Jun;54(2):16
Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47 Suppl 1:
Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci Nov;4(11):

12. Summary of Actions of the Cannabinoids5
Cannabinoid Therapy (nabilone)
Neurotransmitter (NT) from presynaptic neuron activates the postsynaptic neuron. 1
Inhibition of Neurotransmitter Release 2
Activated postsynaptic neuron releases endocannabinoids.
CB1 Receptor 4
Presynaptic Neuron
Endogenous CB1 ligand diffuses back to and binds to the presynaptic CB1 receptor. 3 1
Endogenous Cannabinoid Retrograde Signaling 3
Slide Suggested Narrative—Mechanism of Action of the Cannabinoids
Endocannabinoid signaling is a multi-step process, while exogenous cannabinoids work more directly:
1. Neurotransmitter released from vesicles within the presynaptic neuron activates the postsynaptic neuron
2. Activation of the postsynaptic neuron leads to the biosynthesis and nonvesicular release of an endocannabinoid, likely via a calcium mediated process1-3
3. The endocannabinoid diffuses back to and binds to the presynaptic CB1 receptor3
4. The CB1 receptor activates a G protein which can lead to a number of presynaptic downstream events (e.g., effects on ion currents) that result in the inhibition of neurotransmitter release4,5
5. Exogenous cannabinoids circumvent this multi-step process by directly activating CB1 receptors and stimulating the endogenous cannabinoid system, mimicking or enhancing its natural functions
1Howlett AC, et al. Pharmacol Rev Jun;54(2):16
2Howlett AC, et al. Neuropharmacology. 2004;47 Suppl 1:
3Piomelli D. Nat Rev Neurosci Nov;4(11):
4Diana MA, Marty A. Br J Pharmacol May;142(1):9-19. Epub 2004 Apr 20.
5Freund TF, Katona I, Piomelli D. Physiol Rev Jul;83(3):
6Croxford JL. CNS Drugs. 2003;17(3): 2
CB1 receptor activates a G-protein, leading to inhibition of NT release. 4
Neurotransmitter Receptor
Postsynaptic Neuron 5
Nabilone is thought to activate CB1 receptors directly, mimicking the effects of endocannabinoids.
Endogenous and Exogenous Cannabinoids Reduce Neuronal Signaling
*see notes for references

13. Anti-emetic, Anti-nausea Effects of Cannabinoids

14. Causes of nausea and vomiting/emesis: Viral illness Cancer
Chemotherapy Radiotherapy
Potential Action of Cannabinoids in Nausea and Emesis
Nausea and emesis (vomiting) occur under a variety of conditions, including viral illness, cancer, cancer chemotherapy and radiotherapy. Both are produced by excitation of one or a combination of trigger(s) located in the gastrointestinal tract, brain stem, and higher cortical and limbic centers.{Hornby, 2001} Cannabinoids are thought to exert their therapeutic effects via action on CB1 cannabinoid receptors in all three of these regions, with the best evidence being for effects in the brain.{Hornby, 2001; Dodds, 1985; Croxford, 2003}
References
Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):
Dodds LJ. The control of cancer chemotherapy-induced nausea and vomiting. J Clin Hosp Pharm Jun;10(2):
Hornby PJ. Central neurocircuitry associated with emesis. Am J Med Dec 3;111 Suppl 8A:106S-112S.

15. Dorsal Vagal Complex (DVC)
The Nucleus of the Solitary Tract (NTS) in the DVC receives information about:
Blood-borne emetics via the brainstem (BS) “Chemo-receptor Trigger Zone”
Abdominal irritants via vagal afferents
NTS neurons, in turn, project to a BS central pattern generator, which coordinates vomiting behavior
Dorsal Vagal Complex (DVC)
- NTS
Brainstem Emetic Circuitry: Dorsal Vagal Complex
The central region most implicated in the effects of cannabinoids in the control of emesis is the brainstem dorsal vagal complex (DVC), and in particular the nucleus of the solitary tract (NTS) within the DVC.{Hornby, 2001; Martin and Wiley, 2004} The NTS receives information about blood-borne emetics (such as cytotoxic drugs) via chemosensitive neurons in the area postrema, referred to as the “chemo-receptor trigger zone (CTZ).” It also receives input from abdominal vagal afferents that detect local irritants (such as cytotoxic drugs, radiation, viruses) in the stomach and intestine. Neurons from the NTS, in turn, project to a brainstem central pattern generator, which coordinates the sequence of behaviors during emesis.{Hornby, 2001}
References
Hornby PJ. Central neurocircuitry associated with emesis. Am J Med Dec 3;111 Suppl 8A:106S-112S.
Martin BR, Wiley JL. Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain. J Support Oncol Jul-Aug;2(4):305-14; discussion

16. Cortex Limbic System
Brainstem
Emetic
Circuitry
Higher cortical and limbic regions (governing taste, smell, sight, pain, memory and emotion) can suppress or stimulate nausea/vomiting through descending connections to the BS emetic circuitry
Higher Cortical and Limbic Regions
Cannabinoids are also believed to help control emesis via action in higher cortical and limbic regions that influence the brainstem emetic circuitry. These areas are involved in modulating complex experiences such as taste, smell, sight, and pain, as well as memory (involved in anticipatory nausea/vomiting {Grunberg, 1989}) and emotion (e.g., fear and dread). They can powerfully stimulate or suppress nausea and vomiting. Specific areas implicated include insular cortex, orbital cortex, cingulate cortex, uncus and pes hippocampus, and amygdala.{Fiol et al, 1988; Schauble et al, 2002}
Nabilone (nabilone), a synthetic analog of THC, is indicated for the management of severe nausea and vomiting associated with cancer chemotherapy.{Nabilone (Nabilone) Prescribing Information} The antiemetic action of nabilone may be triggered in the forebrain, causing inhibition of the brainstem emetic circuitry through descending connections.{Ward and Holmes, 1985} Given their sites of action and positive findings in animals, cannabinoids may also be useful as pretreatments to avoid establishment of conditioned nausea and anticipatory emesis associated with chemotherapy.{Fride et al, 2005}
References
Nabilone (Nabilone) Prescribing Information.
Fiol ME, Leppik IE, Mireles R, Maxwell R. Ictus emeticus and the insular cortex. Epilepsy Res Mar-Apr;2(2):
Fride E, Bregman T, Kirkham TC. Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood. Exp Biol Med (Maywood) Apr;230(4):
Grunberg SM. Advances in the management of nausea and vomiting induced by non-cisplatin containing chemotherapeutic regimens. Blood Rev Dec;3(4):
Schauble B, Britton JW, Mullan BP, Watson J, Sharbrough FW, Marsh WR. Ictal vomiting in association with left temporal lobe seizures in a left hemisphere language-dominant patient. Epilepsia Nov;43(11):
Ward A, Holmes B. Nabilone. A preliminary review of its pharmacological properties and therapeutic use. Drugs Aug;30(2):

17. Cannabinoids are thought to exert their antiemetic effects primarily via action on CB1 receptors in the NTS and higher cortical and limbic regions
Indirect, partial actions on 5-HT and DA signaling via 5-HT3 and D2 receptors are implicated
Cortex Limbic System
Brainstem Emetic Circuitry
Potential Action of Cannabinoids in Nausea and Emesis
Nausea and emesis (vomiting) occur under a variety of conditions, including viral illness, cancer, cancer chemotherapy and radiotherapy. Both are produced by excitation of one or a combination of trigger(s) located in the gastrointestinal tract, brain stem, and higher cortical and limbic centers.{Hornby, 2001} Cannabinoids are thought to exert their therapeutic effects via action on CB1 cannabinoid receptors in all three of these regions, with the best evidence being for effects in the brain.{Hornby, 2001; Dodds, 1985; Croxford, 2003}
Brainstem Emetic Circuitry: Dorsal Vagal Complex
The central region most implicated in the effects of cannabinoids in the control of emesis is the brainstem dorsal vagal complex (DVC), and in particular the nucleus of the solitary tract (NTS) within the DVC.{Hornby, 2001; Martin and Wiley, 2004} The NTS receives information about blood-borne emetics (such as cytotoxic drugs) via chemosensitive neurons in the area postrema, referred to as the “chemo-receptor trigger zone (CTZ).” It also receives input from abdominal vagal afferents that detect local irritants (such as cytotoxic drugs, radiation, viruses) in the stomach and intestine. Neurons from the NTS, in turn, project to a brainstem central pattern generator, which coordinates the sequence of behaviors during emesis.{Hornby, 2001}
Higher Cortical and Limbic Regions
Cannabinoids are also believed to help control emesis via action in higher cortical and limbic regions that influence the brainstem emetic circuitry. These areas are involved in modulating complex experiences such as taste, smell, sight, and pain, as well as memory (involved in anticipatory nausea/vomiting {Grunberg, 1989}) and emotion (e.g., fear and dread). They can powerfully stimulate or suppress nausea and vomiting. Specific areas implicated include insular cortex, orbital cortex, cingulate cortex, uncus and pes hippocampus, and amygdala.{Fiol et al, 1988; Schauble et al, 2002}
Nabilone (nabilone), a synthetic analog of THC, is indicated for the management of severe nausea and vomiting associated with cancer chemotherapy.{Nabilone (Nabilone) Prescribing Information} The antiemetic action of nabilone may be triggered in the forebrain, causing inhibition of the brainstem emetic circuitry through descending connections.{Ward and Holmes, 1985} Given their sites of action and positive findings in animals, cannabinoids may also be useful as pretreatments to avoid establishment of conditioned nausea and anticipatory emesis associated with chemotherapy.{Fride et al, 2005}
Gastrointestinal Enteric Nervous System
Finally, cannabinoids inhibit gastrointestinal transit and hence gastric emptying. They decrease fundic tone and antral motility via CB1 receptors in the enteric nervous system, and possibly via action in the DVC. These actions could possibly contribute to the antiemetic effects of cannabinoids. {Hornby, 2001; Croxford, 2003} However, the exact mechanism by which this may occur is unclear.
Modulation of Neuronal Signaling
A variety of neurotransmitter systems are involved in the complex process of nausea/vomiting, and cannabinoids are thought to assert a primarily inhibitory affect on neurotransmitter release.{Schlicker and Kathmann, 2001; Howlett et al, 2002; Freund et al, 2003} Serotonin (5-HT) and dopamine (DA) are involved in transmission of peripheral stimuli to the brainstem,{Hornby, 2001; Dodds, 1985; Grunberg, 1989} Indirect, partial actions on 5-HT and DA neurotransmission via 5-HT3 and D2 receptors have been implicated in cannabinoid antiemetic effects.{Nahas et al, 2002} The antiemetic action of nabilone is not believed to be mediated primarily by a DA path, however, although there may be some activity at the CTZ.{Ward and Holmes, 1985}
References
Nabilone (Nabilone) Prescribing Information.
Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs. 2003;17(3):
Dodds LJ. The control of cancer chemotherapy-induced nausea and vomiting. J Clin Hosp Pharm Jun;10(2):
Fiol ME, Leppik IE, Mireles R, Maxwell R. Ictus emeticus and the insular cortex. Epilepsy Res Mar-Apr;2(2):
Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev Jul;83(3):
Fride E, Bregman T, Kirkham TC. Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood. Exp Biol Med (Maywood) Apr;230(4):
Grunberg SM. Advances in the management of nausea and vomiting induced by non-cisplatin containing chemotherapeutic regimens. Blood Rev Dec;3(4):
Hornby PJ. Central neurocircuitry associated with emesis. Am J Med Dec 3;111 Suppl 8A:106S-112S.
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev Jun;54(2):
Martin BR, Wiley JL. Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain. J Support Oncol Jul-Aug;2(4):305-14; discussion
Nahas G, Harvey DJ, Sutin K, Turndorf H, Cancro R. A molecular basis of the therapeutic and psychoactive properties of cannabis (delta9-tetrahydrocannabinol). Prog Neuropsychopharmacol Biol Psychiatry May;26(4):
Schauble B, Britton JW, Mullan BP, Watson J, Sharbrough FW, Marsh WR. Ictal vomiting in association with left temporal lobe seizures in a left hemisphere language-dominant patient. Epilepsia Nov;43(11):
Schlicker E, Kathmann M. Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci Nov;22(11):
Ward A, Holmes B. Nabilone. A preliminary review of its pharmacological properties and therapeutic use. Drugs Aug;30(2):
Dorsal Vagal Complex
- NTS

18. Summary
CB agonists act as Omnineuromodulators —a term that describes their role in activating CB1 endocannabinoid receptors, which are omnipresent throughout the CNS and modulate neuronal signaling
Evidence shows that Omnineuromodulation underlies the therapeutic role of CB agents in the treatment of CINV, Cachexia, and Neuropathic Pain

19. Approved License for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional anti-emetic treatments

20. Nabilone delivers:1
Convenient BID dosing: The usual adult dosage is 1 or 2 mg BID
Predictable pharmacokinetics: Peak plasma concentrations occur within 2 hours following oral administration
Long acting: 8 to 12 hour duration of action
Not detected by the EMIT test2
In anti-emetic phase III studies, involving 316 cancer patients receiving a variety of chemotherapeutics (including cisplatin), nabilone was shown to be superior in efficacy to placebo, as well as to prochlorperazine, in:1
Reduction of vomiting episodes
Reduction of nausea severity
Improvement in appetite
Investigators’ global impression of efficacy3
*see notes for references
References
NabiloneTM (nabilone) Package Insert.
Fraser AD and Meatherall R. Lack of intereference by nabilone in the EMIT d.a.u. cannbiniod assay, Abbot TDx Cannabiniod Assay and a sensitive TLC assay for 9-THC-carboxylic acid. J Analytic Tox 1989:
3. Data on File: Protocol #20 and #28. Valeant Pharmaceuticals.

21. Nabilone Pivotal Studies

22. Placebo-Controlled, Fixed-Dose Trials
Primary Endpoint: Patient-Rated Efficacy Criteria
Suggested Narrative—Placebo-Controlled, Fixed-Dose Trials
Six placebo-controlled fixed-dose registration trials (N=129) conducted assessing the efficacy of Nabilone demonstrated the superiority of Nabilone over placebo.
Since the most intense cancer chemotherapy treatment usually occurred on the first day of each cycle, when multiple anticancer agents were most commonly administered, efficacy criteria were also evaluated on Day 1.
Both the average number of vomits and the number of vomits on day 1 were more than double in the placebo group compared with the Nabilone group (P<.01 for average frequency of vomiting)
Similarly, severity of nausea in the Nabilone group was nearly half that in the placebo group (P<.001 for average nausea severity).
Reduction in vomiting and lessening of the severity of nausea translated into increased food intake—both on average during the studies and on day 1.
Number of vomits
Nausea severity: 0=none, 1=mild, 2=moderate, 3=severe
Food intake: 0=none, 1=less than usual, 2=usual amount or average, 3=more than usual
Data on File: Protocols 9, 20 and 28. Valeant Pharmaceuticals International.

23. Active-Controlled, Fixed-Dose Trials
Primary Endpoint: Patient-Rated Efficacy Criteria
Suggested Narrative—Active-Controlled, Fixed-Dose Trials
In active (prochlorperazine)-controlled, fixed-dose, crossover registration studies (N=75), the frequency of vomiting and severity of nausea were significantly (P<.007) reduced with Nabilone therapy compared with that of prochlorperazine.
Since the most intense cancer chemotherapy treatment usually occurred on the first day of each cycle, when multiple anticancer agents were most commonly administered, efficacy criteria were also evaluated on Day 1.
The average dosage of Nabilone was 2 mg B.I.D., while that of prochlorperazine was 10 mg B.I.D.
Reduced frequency of vomiting and less severe nausea resulted in increased food intake in the Nabilone subjects.
Number of vomits
Nausea severity: 0=none, 1=mild, 2=moderate, 3=severe
Food intake: 0=none, 1=less than usual, 2=usual amount or average, 3=more than usual
Data on File: Protocols 9, 20 and 28. Valeant Pharmaceuticals International.

24. Active-Controlled, Fixed-Dose Trials
Primary Endpoint: Investigator-Rated Efficacy and Safety
Suggested Narrative—Active-Controlled, Fixed-Dose Trials
Investigators rated their global impressions of treatment during active (prochlorperazine)-controlled, fixed-dose registration trials (N=75).
Both efficacy and safety of Nabilone were superior to those of prochlorperazine, according to the investigators’ ratings.
Efficacy: 1=very good, 2=good, 3=fair, 4=poor, 5=very poor
Safety: Based on the frequency of adverse events
Data on File: Protocols 9, 20 and 28. Valeant Pharmaceuticals International.

25. Active-Controlled, Flexible-Dose Trial
Primary Endpoint: Patient-Rated Efficacy Criteria
Suggested Narrative—Active-Controlled, Flexible-Dose Trial
Nabilone was compared with prochlorperazine in a flexible-dose, crossover trial.
Since the most intense cancer chemotherapy treatment usually occurred on the first day of each cycle, when multiple anticancer agents were most commonly administered, efficacy criteria were also evaluated on Day 1.
Daily doses of Nabilone that exceeded 4 mg were not uncommon.
Benefits of Nabilone were observed on day 1 of chemotherapy.
Over 2 cycles of chemotherapy, Nabilone demonstrated significant reduction in vomiting frequency and nausea severity (P<.001 for effects on both vomiting and nausea).
Number of vomits
Nausea severity: 0=none, 1=mild, 2=moderate, 3=severe
Food intake: 0=none, 1=less than usual, 2=usual amount or average, 3=more than usual
Data on File: Protocols 9, 20 and 28. Valeant Pharmaceuticals International.

26. Patients Prefer Nabilone
Placebo-Controlled, Fixed-Dose Trials
Active-Controlled, Fixed-Dose Trials
77%
73%
12%
20%
Suggested Narrative—Patients Prefer Nabilone
In both the placebo-controlled and active-controlled, fixed-dose trials, patients were asked to indicate their treatment preference.
Overwhelmingly, patients preferred Nabilone over both placebo and prochlorperazine.
In the active-controlled, flexible-dose crossover trial, of the patients who received Nabilone, 54.2% (n=52) continued with Nabilone on an open-label basis.
Of these patients, 88.5% (n=46) reported side effects (primarily “high” and vertigo) while taking Nabilone on crossover.
Thus, despite the high incidence of side effects, the majority of patients continued Nabilone therapy.
12% 7%
Preferred Nabilone
Preferred Nabilone
Preferred Placebo
Preferred Prochlorperazine
No Preference
No Preference

27. Summary: Nabilone and Reduction of Vomiting Frequency
Chemotherapy -
Induced
Nausea
and Vomiting
Suggested Narrative—Summary: Nabilone and Reduction of Vomiting Frequency

28. Nabilone Reduces the Frequency of Vomiting
Reduction in Frequency of Vomiting
N=129
*P < 0.01
N=75
**P < 0.007
Suggested Narrative—Nabilone Reduces the Frequency of Vomiting
The bar graphs visually demonstrate the efficacy of Nabilone in reducing the frequency of vomiting.
Compared with both placebo and prochlorperazine, Nabilone significantly reduced the frequency of vomiting (P<.01 and P<.007, respectively).
Nabilone
Placebo
Nabilone
Prochlorperazine
Data on File: Protocol #9, #20, and #28. Valeant Pharmaceuticals North America.

29. Nabilone Significantly Reduces Vomiting Frequency
Suggested Narrative—Nabilone Significantly Reduces Vomiting Frequency
Objective
Evaluate the effectiveness of nabilone compared with that of prochlorperazine in patients (N=80) receiving chemotherapy
Design
Most patients were receiving cisplatin-based chemotherapy
Patients received 1 of 2 antiemetic regimens in the first cycle of chemotherapy and crossed over to the 2nd antiemetic regimen during the 2nd chemotherapy cycle
Results
Nabilone reduced vomiting by approximately 33% on all days of chemotherapy
The effectiveness of Nabilone was more pronounced after the first day of chemotherapy
On day 5, the mean number of vomiting episodes in patients receiving Nabilone was 1.12
The patients’ preference for Nabilone was statistically significant (P<.001)
46 of 60 patients preferring Nabilone required further chemotherapy; all patients continued Nabilone therapy for a total of 76 course
Safety and Toxicity
Did not preclude antiemetic therapy
Did not interfere with completion of chemotherapy
Einhorn LH, et al. J Clin Pharmacol. 1981;21:64S-69S.
Einhorn LH, et al. J Clin Pharmacol. 1981;21:64S-69S.

30. Nabilone: Superior to Prochlorperazine in Patients with Severe CINV
Suggested Narrative—Nabilone: Superior to Prochlorperazine in Patients with Severe CINV
Objective
Test the efficacy of nabilone for use in cancer patients compared with that of prochlorperazine in patients (N=113) with severe CINV
Design
Two double-blind, crossover trials
Patients received 1 of 2 antiemetic regimens in the first cycle of chemotherapy and crossed over to the 2nd antiemetic regimen during the 2nd chemotherapy cycle
Dosages employed at two study centers
2 mg nabilone or 10 mg prochlorperazine q8hr beginning two doses before chemotherapy – or
2 mg nabilone or 10 mg prochlorperazine q6hr beginning 30 minutes before chemotherapy
Results
Overall, 80% of patients responded to Nabilone therapy versus 32% for prochlorperazine (P<.001)
Patients significantly favored Nabilone for continued use (P<.001)
Safety
Predominant side effects—somnolence, dry mouth, and dizziness—were similar for both agents but occurred more often with nabilone therapy
4 patients receiving prochlorperazine and 5 patients receiving nabilone discontinued therapy due to the occurrence of unacceptable side effects
Euphoria associated with Nabilone therapy occurred infrequently and was mild in intensity
Herman TS, et al. N Engl J Med. 1979;300:
CR=complete response; PR=partial response
Herman TS, et al. N Engl J Med. 1979;300:

31. Summary: Nabilone and Reduction of Vomiting Frequency
CINV is an established indication for Nabilone
Clinical trials have confirmed the efficacy of Nabilone in reducing frequency of vomiting in cancer patients receiving chemotherapy
Nabilone is an important addition to the physician’s armamentarium against the nausea and vomiting associated with chemotherapy in patients who have failed to respond adequately to conventional antiemetic therapy
Suggested Narrative—Summary: Nabilone and Reduction of Vomiting Frequency

32. Nabilone: In reduction of NauseaV
Chemotherapy -
Induced
Nausea
Suggested Narrative—Nausea: A Continued Challenge in the Cancer Patient

33. Control of Nausea Cannabinoids: A Systematic Review
30 randomized, comparative studies of cannabinoids with placebo or other antiemetics
(oral Nabilone [nabilone]= 16 studies; oral dronabinol=11 studies; intramuscular levonatrodol=1 study)
Suggested Narrative—Control of Nausea. Cannabinoids: A Systematic Review
Design
Quantitative systematic review, using 30 randomized studies identified through a literature search to August 2000.
Cannabinoids were more effective than:
Prochlorpromazine
Thiethylperazine
Haloperidol
Domperidone
Alizapride
6 to 8 patients needed to be treated with cannabinoids for complete control, had they all received a conventional antiemetic.
Active control= prochlorperazine, metoclopramide, chlorpromazine, haloperidol, domperidone, and alizapride
Tramèr MR, et al. BMJ. 2001;323:1-8.

34. Comparative Efficacy of Nabilone vs. Prochlorperazine
Suggested Narrative—Comparative Efficacy of Nabilone vs. Prochlorperazine
*Based on patients’ report (daily average): 0=none; 1=mild; 2=moderate; 3=severe
Data on File: Protocol #9, #20, and #28. Valeant Pharmaceuticals North America.

35. Nabilone Significantly Reduces Nausea Severity
Suggested Narrative—Nabilone Significantly Reduces Nausea Severity
Results
Compared with prochlorperazine, Nabilone significantly decreased the severity of nausea
The effects of Nabilone were more pronounced after the first day; by day 3, the mean nausea score was 0.86 (0=none; 1=mild)
Score: 0=none; 1=mild; 2=moderate; 3=severe
Einhorn LH, et al. J Clin Pharmacol. 1981;21:64S-69S.

36. Severity of Nausea Significantly Reduced with Nabilone
Suggested Narrative—Severity of Nausea Significantly Reduced with Nabilone
Ahmedzai S, et al. Br J Cancer. 1983;48:

37. Summary: Nausea Nausea is more difficult to control than is vomiting
Control of nausea remains a significant unmet need in cancer patients receiving chemotherapy
Nabilone has demonstrated efficacy in reducing the severity of nausea
Patients prefer Nabilone over placebo and active controls (prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, alzapride)
Suggested Narrative—Summary: Nausea
The efficacy of Nabilone in reducing the frequency of vomiting and lessening the severity of nausea in cancer patients receiving chemotherapy, as well as the substantial proportion of patients who indicated a preference for cannabinoid therapy in numerous clinical trials validate its importance in the treatment of refractory nausea and vomiting

38. Other benefits: Impact of Nabilone on Pain
A Retrospective Chart Review
Several reductions in acute pain exacerbations and nighttime pain
Relief within 1 week of beginning Nabilone (n=1)
Patients’ testimonial
Taking Nabilone at night made pain more localized, and relief lasted until the following afternoon
Nabilone made pain “livable”
Nabilone “takes the edge off”
Suggested Narrative—Impact of Nabilone on Chronic Pain
Objective
To describe pain responses and adverse events in patients (n=20) with chronic pain who received nabilone over a 4-year period (mean duration of therapy: 1.5 yrs)
Dosage
All patients began nabilone therapy at 1 mg at night
Dosage was increased to 1 mg B.I.D. if tolerated
Some patients required 2 mg B.I.D. to achieve pain relief
Patients taking 1 mg T.I.D. or 2 mg B.I.D. reported more improvement in sleep
Side Effects
No serious adverse events
3 patients discontinued nabilone due to palpitations, dry mouth, increased urinary retention
Berlach DM, et al. Am Acad Pain Med. 2006;7:25-29.
Berlach DM, et al. Am Acad Pain Med. 2006;7:25-29.

39. Other Benefits of Nabilone
3 patients continued to take Nabilone for benefits other than pain relief
Improvement in quality or duration of sleep
Decreased nausea or vomiting
Suggested Narrative—Other Benefits of Nabilone
Patients used other medications concurrently with nabilone, ranging from opioids to antidepressants and procedures such as trigger point injections
During follow-up:
Amitriptyline dose decreased in 1 (pain unchanged)
Morphine sulfate contin dose decreased in 1 (pain unchanged)
Opioid dose increased in 2 (reduced pain)
Opioids rotated in 2 (pain unchanged)
Antidepressant added in 1 (reduced pain)
Berlach DM, et al. Am Acad Pain Med. 2006;7:25-29.
Sleep improvements (n=1)
Decreased nausea & increased appetite (n=1)
Decreased nausea and vomiting and increased sleep (n=1)
50% of patients
25% of patients
Berlach DM, et al. Am Acad Pain Med. 2006;7:25-29.

40. Benefits of Cannabinoids in Cancer Patients: A Retrospective Case Study
Methodology
Suggested Narrative—Benefits of Cannabinoids in Cancer Patients: A Retrospective Case Study
To evaluate the benefits of Nabilone on symptom management in cancer patients,
Charts from patients referred to a palliative care center from July 1, 2005 through June 30, 2006 were retrieved
All patients presented in the advanced stages of their malignancies, and their disease had been deemed incurable by their treating oncologists.
The primary study inclusion criterion was completion of the Edmonton Symptom Assessment System (ESAS) questionnaire on initial consultation and at one or more evaluations thereafter.
Data was subsequently extracted from an Anonymised electronic medical record system that was developed by the principal author.
All patients were managed by a specialist team including a palliative medicine physician and nurse practitioner.
The decision to prescribe Nabilone was based on the presence of severe distress on the initial consultation, as reflected by high numeric rating scores for the various parameters that comprise the ESAS tool. In addition, those same patients had also provided a history of refractory symptoms despite the use of other pain and symptom management agents.
The use, discontinuance, and dosage of Nabilone, which was prescribed at the discretion of the consulting palliative medicine physician, were documented.
Of the 139 subjects who met study criteria, 65 had received Nabilone vs. 57 who received no cannabinoid therapy and 17 who discontinued Nabilone therapy
Sixty-five patients employed upwardly titrated doses of Nabilone throughout the follow-up period. The average daily dose of Nabilone for this group was 1.83 mg/day (+0.92 mg/day).
The mean duration from baseline to last ESAS score was 59.2 days (+78.4) in all patients, 44.9 days (+60.7) in the non-Nabilone group, 58.0 days (+83.6) in the Nabilone group and days (+92.0) in those who discontinued Nabilone therapy.
*Data on file

41. Edmonton Symptom Assessment System (ESAS)
Suggested Narrative—Edmonton Symptom Assessment System
The ESAS is a 10-item, patient- or caregiver-rated, validated tool used to assess symptoms in palliative care patients.
The severity of the 10 items is rated on a 10-point scale where 0 indicates absence of the symptom and 10 reflects worst possible severity of the symptom.
The symptoms are rated at the time of the assessment; thus, obtaining baseline and serial ESAS scores provides a profile of symptom severity over time. The sum of the 10 items is the “distress score,” which ranges from 0 for no distress to 100 for worst possible distress.

42. Reasons for Cannabinoid Discontinuation
12/17 (71%) due to side effects
Drowsiness
Dizziness
Delirium
5/17 (29%) advised by other MDs
Discontinuation Rate:
Overall = 20.7%
Adjusted = 14.6%
Suggested Narrative—Reasons for Cannabinoid Discontinuation
Of the 17(20.4%) subjects who discontinued Nabilone, 12(14.6%) did so owing to severe side effects that included drowsiness, dizziness, delirium, and dry mouth. All of the latter totally resolved within 24 hours of discontinuation of Nabilone. Five patients elected to stop Nabilone despite not citing any specific side effects, based on the advice of other physicians involved in their care who felt that Nabilone was not indicated, or felt uncomfortable with its off-label usage.

43. Differentiating Between the Cannabinoids: Pharmacokinetics
Nabilone
Marinol
Oral Dosing
1-2 mg 1-3 hrs before chemotherapy, and 2 times per day for up to 48 hrs afterwards
5 mg/m2 1-3 hrs before chemotherapy, and every 2-4 hrs afterwards for a total of 4-6 doses per day
Source
Synthetic ∆9-THC analog
Synthetic ∆9-THC
Formulation
Crystalline powder capsule
Capsule formulated with sesame oil, among other ingredients (contraindicated in patients with a hypersensitivity to sesame oil)
Onset of Action
60-90 min
30-60 min
Peak plasma concentrations (Tmax)
2 hrs
2-4 hrs
Duration of Action
8-12 hrs
4-6 hrs for psychoactive effects
Metabolites
2 active metabolites
2 active metabolites and more than 20 other metabolites
Clearance
Major excretory pathway is the biliary system
Biliary excretion is major route of elimination
Suggested Narrative—Differentiating Between the Cannabinoids: Pharmacokinetics
The pharmacokinetics Nabilone and Marinol are similar in several respects yet differ in important ways:
The duration of action of Nabilone is longer than that of Marinol, which translates into less frequent dosing for Nabilone (twice daily vs. up to 6 times daily)
Nabilone has only 2 active metabolites, versus more than 20 for Marinol, which might suggest an improved safety profile of Nabilone
NabiloneTM (nabilone) Package Insert. Valeant Pharmaceuticals North America; Marinol® (dronabinol) Package Insert. Solvay Pharmaceuticals, Inc.

44. Cannabinoid Metabolism
CYP450 Metabolizing Enzymes
CYP450 Enzyme Inhibition
CYP450 Enzyme Induction
Nabilone
2C9*, 3A4
(aldehyde oxygenase)
None to Date
Marinol
2C9*, 2C11, 3A4
3A4
*Main metabolizing isoenzyme
Metabolized principally through the CYP450 2C9 isoenzyme
No inhibitory or inducing effect on any of the isoenzymes
Competes with very few medications at the metabolic level, including opioids
Examples of medications metabolized by CYP3A4: anti-fungals, methadone, many anti-depressants, HIV protease inhibitors
Suggested Narrative—Cannabinoid Metabolism
Nabilone is metabolized principally via the cytochrome P450 2C9 isoenzyme, which means:
No inhibitory or inducing effect on any of the isoenzymes
Competes with very few medications at the metabolic level, including opioids
Examples of medications metabolized by CYP3A4: anti-fungals, methadone, many anti-depressants, HIV protease inhibitors
Nabilone
Nahas GG, Surim KM, Harvet DJ, Agurell S, eds. Marihuana and Medicine. Totowa, NJ: Human Press; 1999:

45. Safety Overview of Cannabinoids
Cannabinoids should not be taken with alcohol, sedatives, hypnotics, or other psychoticomimetic substances
Nabilone™
MARINOL® (dronabinol)
Contraindications
In patients with a history of hypersensitivity to any cannabinoid
In patients with a history of hypersensitivity to any cannabinoid or sesame oil
Most Commonly Occurring Adverse Effects
Drowsiness
Vertigo
Dry mouth
Euphoria
Ataxia
Headache
Concentration difficulties
Asthenia
Palpitations
Tachycardia
Vasodilatation/facial flush
Abdominal pain
Nausea
Vomiting
Amnesia
Ataxia
Confusion
Depersonalization
Dizziness
Euphoria
Paranoid reaction
Somnolence
Thinking abnormal
Suggested Narrative—Safety Overview of Cannabinoids
Nabilone (NabiloneTM) Package Insert; San Diego, Valeant Pharmaceuticals North America; 2006; Dronabinol (Marinol® ) Package Insert. Marietta, Ga: Solvay Pharmaceuticals, Inc.; 2003.

46. Unique MOA of Cannabinoids Clinical Trial Results
Summary
Treatment Challenges
Unique MOA of Cannabinoids
Clinical Trial Results
CINV—a highly prevalent side effect of cancer treatment
Persistent CINV is associated with several adverse sequelae
Pain is often under-diagnosed and under-treated
Target ubiquitous CB receptors in the CNS and periphery
CINV: agonism of CB1 receptors inhibits neurotransmitters
Pain: neuromodulatory effects involving both CB1 and CB2 receptors
Support the use of cannabinoids to treat refractory CINV
Suggest that cannabinoids may be useful adjunctive therapy for pain
Suggested Narrative—Summary

47. END SLIDE
QUESTIONS?

49. Adverse Events can be reported to the drug safety
department at Valeant Pharmaceuticals at