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Medical Cannabis E Drug Science Perspective Medical Cannabis e Drug Science Perspective Part 2 - e Endocannabinoid System Drug Science Endocannabinoids Phytocannabinoids Found naturally in your body Found in the cannabis plant There are 2 main classes of endogenous ligand There are over 100 cannabinoids present in within the endocannabinoid system; esters and the cannabis plant, many of which may have amides. They are produced by two distinct therpeutic potential, or may contribute enzymatic systems, act locally, and are rapidly towards the therapeutic effect of ∆9-THC and broken down by hydrolases. They appear to CBD through what is known as the have an important role in neuromodulation ‘entourage effect’ - where compounds work and may be disrupted in various disease states synergistically to produce their effect Most well researched endocannabinoids: Most well researched phytocannabinoids: 2-Arachidonoyl Glycerol (2-AG) Anandamide (AEA) Tetrahydrocannabinol (THC) Cannabidiol (CBD) Basal transmission Stress induced Psychoactive Non-intoxicating HO O O HO HO N O HO HO H H H H H O HO Drug Page 2 of 19 Science Cannabinoid Receptors Endocannabinoids primarily function through two G protein-coupled receptors (GPCRs): CB1 and CB2 receptors. Both receptors have seven transmembrane spanning domains, and couple to the Gi/o family of G proteins. Activation inhibits adenylyl cyclase (AC), subsequently reducing cellular cAMP levels, an important intracellular messenger. The main difference between CB1 and CB2 receptors is their distribution. CB1 receptors are expressed throughout the body. They are one of the most abundant GPCRs in the brain, found primarily on presynaptic terminals of neurons. CB1 receptors are also present on astrocytes, C where they modulate synaptic transmission and plasticity. i/o CB2 receptors are abundantly expressed in peripheral organs with immune function, cP including macrophages, spleen, tonsils, thymus, and leukocytes. Drug Page 3 of 19 Science CB1 Expression in the Brain h disribuion o CB1 rcpors ihin h brin corrs ih is ro in h conro o moor uncion, cogniion, mmor, ppii nd pin Cerebral Cortex Higher Functions Hypothalamus Basal Ganglia Appetite Movement Cerebellum Movement Hippocampus Learning, memory Spinal Cord and stress Peripheral sensation Medulla and pain Nausea and vomiting Drug Page 4 of 19 Science Neuronal Signalling Usually, neurotransmitters travel from the presynaptic bouton CLICK HERE TO across the synaptic cleft to act on postsynaptic receptors WATCH A VIDEO REMINDER OF HOW Example of excitatory transmission NEURONAL Pre Post Presynaptic Postsynaptic https://www.youtube.com/watch?v=BbUcWbtVjT4SIGNALLING WORKS Ca2+Ch. neurone neurone 1. Ca2+ Na+ + + + Na Dendrites Glu GluR Na+ Ca2+Ch. 2. Axon + Na + + Na + Na+ Glu + GluR + Synaptic terminal Ca2+Ch. Cell + 3. + body + + Na+ + + ++ Na + Na+ Nucleus Glu + GluR + + Drug Page 5 of 19 Science Cannabinoid Signalling Drug Cannabinoids signal retrogradely; they diffuse backwards from the postsynaptic to Science the presynaptic neurone, where they stimulate CB1 receptors. Activation reduces presynaptic activity allowing cannabinoids to modulate other signalling systems Pre Post Ca2+Ch. 1. + CB1 R 2-AG + Depolarisation Glu mGluR activation Ca2+Ch. 2. 3. Activation of CB1 leads to presynaptic: CB1 R 2-AG Glu Inhibition of Ca2+channels Inhibition of K+ channels Ca2+Ch. 3. Activation of survival 2-AG pathways CB1 R Endocannabinoids act to Glu inhibit presynaptic release Page 6 of 19 2-Arachidonoyl Glycerol & Anandamide Unlike most other neurotransmitters, endocannabinoids are not stored in vesicles, but are produced on demenad by enzymes in response to an increase in intracellular calcium 2-Arachidonoyl Glycerol (2-AG) Anandamide (AEA) Present at relatively high levels Present at very low levels and has a within the central nervous system very short half-life Responsible for basal Formation is induced by stress endocannabinoid signalling Is a much more potent agonist Is much less effective at activating (activator) of CB1 receptors CB1 receptors and can sometimes anatgonise (block) the effects of 2-AG HO O O HO HO O N H Drug Page 7 of 19 Science Endocannabinoid Formation and Breakdown Modulating the metabolism of endocannabinoids can increase their concentration and duration of activity, providing important therapeutic targets Phosphatidylinositol- Lipid Phosphatidylethanolamine (PE) 4,5-bisphosphate (PIP2) precursors Phospholipase C (PLC) N-acyltransferase (NAT) N-arachidonoyl phosphatidylethanolamine Diacylgycerol (DAG) (NAPE) Diacylglycerol lipase а or в NAPE-specific phospholipase D (DAGLa/B) 2-AG Endocannabinoids AEA Monoacylglycerol lipase (MAGL) Fatty acid amide hydrolase (FAAH) Arachadonic acid Arachadonic acid Degradation + products + Glycerol Ethanomide Drug Page 8 of 19 Science Modulating CB1 Receptors Example schematic of how a Positive and negative allosteric modulators enhance or decrease negative allosteric modulator (NAM) works the effects of endogenous ligands by binding to a different site on their receptor (’allo’- means ‘other’), and changing its shape. This Pre Post may change the ability of the ligand to bind to the receptor, or CB1 R could alter the downstream effects of the ligand. 2-AG Allosteric modulators are useful as they only have an effect when the endogenous ligand is present, therefore maintaining the Glu temporal and spatial characteristics of endogenous signalling. NAM Various positive and negative allosteric modulators of the CB1 receptor have been described. These compounds have been CB1 R reported to result in a more precise modulation of different CB1 signalling pathways, giving them therapeutic potential 2-AG with reduced side effects. Examples of CB1 allosteric modulators include: PSNCBAM-1 Glu Therapeutic Weight loss Org27569 applications compounds ZCZ011 could include: GAT211 Analgesics Drug Page 9 of 19 Science Modulating Formation of 2-AG PIP2 DAGLa is widely expressed throughout neurones. DAGLa knockout reduces microglia activation but causes defecits in PLC synaptic plasticity and a reduction in 2-AG concentrations. B DAGL is expressed predominantly in microglia. DAGL B B Diacylgycerol knockout reduces microglia activation without reducing 2-AG or altering synaptic plasticity. DAGLa/B DAGLB shows potential as a target for inflammatory pain 2-AG A B 4 20 DAGL-β +/+ DAGL-β -/- **** 2 15 MAGL 1 10 (Grams) 0.5 5 **** Lifting (s) Paw Stimulus IntensityStimulus Arachidonic Acid 0.25 0 + Glycerol Control Paw LPS Paw Control Paw LPS Paw Adapted from Wilkerson et al 2017. Using a lipopolysaccharide (LPS)-induced pain model, Wilterson et al show that DAGLB knockout mice do not develop mechanical (A) or cold (B) allodynia. Drug Page 10 of 19 Science Modulating Breakdown of 2-AG 2-AG is a full agonist at CB1/CB2. Inhibiting its breakdown PIP leads to increased activity in the endocannabinoid system, 2 but also leads to a reduction in arachidonic acid production PLCB MAGL Inhibitors (JZL184) Diacylgycerol Reduce pain Reduce Seizure behaviours DAGL Activity a/B Reduce 2-AG anxiety-like Reduce morphine behaviours and nicotine withdrawal MAGL Cancer suppression ECB mediated Arachidonic Acid Reduced + Glycerol neuro-inflammation Non-ECB mediated Mild side effects including some sedation and cognitive deficits Drug Page 11 of 19 Science Modulating Breakdown of Anadamide PE Anandamide is a partial agonist at CB1/CB2. Inhibiting its breakdown also has therapeutic potential by increasing activity within the endocannabinoid system NAT FAAH Inhibitors NAPE (PF-8345) NAPE-PLD Enhance social Efficacy in human behaviours in ASD cannabis abuse models AEA disorder FAAH Reduce nicotine addiction Arachidonic Acid Reduce depression and + Ethanomide anxiety-like behaviours Very mild side effect profile in humans and animals Drug Page 12 of 19 Science Exogenous Phytocannabinoids THC A partial agonist at CB1 and CB2 receptors and is the main intoxicant in cannabis. Depending on the physiological HO environment, it can sometimes increase or decrease the activity of the H endocannabinoid system. H THC has been linked to earlier onset of Schizophrenia and psychosis. O Dronabinol and Nabilone Synthetic derivatives of THC Can be used to treat chemotherapy emesis Drug Page 13 of 19 Science Exogenous Phytocannabinoids CBD Cannabidiol is a negative allosteric modulator of CB1. It alters the shape of CB1 which prevents activation by endocannabinoids. HO H It does not have any psychoactive effects - it has even shown promise in reducing psychotic symptoms in H patients with Schizophrenia. HO Epidiolex CBD oil derived from cannabis Can be prescribed for children with rare epilepsy Drug Page 14 of 19 Science Why We Need More Research Individual phytocannabinoids and their synthetic derivatives have very different outcomes in different disease states. Individual patients with the same condition also show varied responses to the same CBMPs; better understanding and more varied combinations of cannabinoids are needed to improve available treatments. The example of cannabinoids in Huntington’s: CB1 expression decreases in (healthy) Huntingtons positive neurons (diseased) CBD, AEA, 2-AG and WIN55 212-2 (a synthetic cannabinoid with similar effects to THC) increases CB1 expression and cell survival. THC and CP55 940 (a synthetic cannabinoid) reduce CB1 expression and decrease cell survival. Drug Page 15 of 19 Science Why We Need More Research The brain continues to develop throughout adolescence and into the early twenties, in particular there is significant synaptic maturation, pruning and
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