The complex pharmacology of cannabis Ben J. Whalley [email protected] 28 June 2013 © University of Reading 2009 www.reading.ac.uk/cinn Outline • Constituents of cannabis – Cannabinoids and non-cannabinoids – Historical changes in composition • The endocannabinoid system – The physiological system affected by THC – Dispelling myths aka ‘Just because it has ‘cannab’ in the name…’ – Cannabinoids that do act via the endocannabinoid system • Beyond the endocannabinoid system – Cannabinoids that don’t act via the endocannabinoid system • Considerations for human medical development and use – Modulating the ubiquitous – Natural ≠ safe – Winning strategies: ‘Smaller & Quicker’ or ‘Slower & Larger’? [email protected] 2 Constituents of cannabis • Cannabis: for the most part, we are talking about the plant Cannabis sativa. • You’ve probably gathered that it one of the most widely used recreational and medicinal drugs worldwide. – ~150 million people smoking cannabis daily (WHO) • May be the first non-food plant cultivated by humans (~8000 BC)[2]. • Best known for its psychoactive constituent, Δ9- tetrahydrocannabinol (‘THC’). [email protected] Much, much more than just D9-THC • In addition to D9-THC, cannabis also contains: • >100 other ‘cannabinoids’ – Cannabinoids are chemical entities that are structurally similar to THC[3]. – phenol ring, 5-carbon alkyl chain, central pyran ring and mono- unsaturated cyclohexyl ring. – Not found in any other plant. • >400 other non-cannabinoids[3]. – Cannot rule out specific effects of these non-cannabinoids. – e.g. Eugenol: acts at similar receptors in the brain as other drugs (e.g. alcohol; GABAAR). [email protected] Constituents of cannabis II Biosynthesis of phyto cannabinoids Hexanoyl CoA Acetyl CoA Olivetolic acid Cannabigerolic acid Cannabinerolic acid THC acid CBD acid CBC acid THC CBD CBC … tetrahydrocannabinol cannabidiol cannabichromene From [4] >30 more found since this paper was published in 2005… Exist as the acid form in the plant and are decarboxylated by smoking and/or storage [email protected] A brief detour into history and human nature… • Historical/ancient use of psychoactive drugs relied upon the raw plant material or very crude extracts. – E.g. Hashish from marijuana, shamanic drinking of reindeer urine after feeding animals Amanita muscaria • Human nature seems to aspire towards more purified and potent end products…often with unintended consequences. Historical Contemporary Marijuana/hashish Skunk (breeding)/hash oil Psilocybe semilanceata (‘Magic LSD mushrooms’), peyote Coca leaves Cocaine/crack cocaine Opium (crude extract) Heroin [email protected] Cannabis breeding/’genetics’ • ‘Genetics’ sounds modern and post-human genome project; for cannabis, it’s not. • Cannabis genetics are based around classical Mendelian, inheritance-driven breeding of plants. • Male/female plants and easy cloning (‘taking cuttings’) allow for straightforward experimental breeding to optimise for specific cannabinoid compositions • Recreational use is ~2-3x alleged medicinal use; the majority of breeding has focussed upon optimising D9-THC levels for psychoactivity at the expense of other cannabinoids. – Strong suggestions of over-emphasis of medicinal use and positive reporting bias. • Some ‘medicinal’ growers starting to focus upon strains with higher CBD levels but still significant D9-THC present. – Risks associated with D9-THC – Undesirable side effect profile – Particular risks in paediatrics (permanent ~10 point IQ drop) http://www.genetics.org/content/163/1/335.full.pdf [email protected] 7 The endocannabinoid system in a nutshell • The endocannabinoid systems was first described in the late 1980s/early 1990s • Comprises endogenous ligands, Anandamide 2-arachidonoyl glycerol (2-AG) receptors, synthesic and degradation enzymes • Cannabinoid receptors: – cell surface receptors – present on a wide variety of cell types. – two CBR types: • CB1: principally in the CNS, affect neuronal excitability by modulating neurotransmitter release • CB2: principally in non-brain areas and linked to immune response • Endocannabinoids: – Two principal ECs thus far identified: • anandamide • 2-arachidonoyl glycerol 8 [email protected] It’s a little more complicated than that... [email protected] 9 But it’s got ‘cannab-’ in the name... • The endocannabinoid system was so named because the CB1 receptor is the target for D9-THC. – This does not mean that all cannabinoids act via the endocannabinoid system! • Numerous synthetic ligands for CB1Rs and CB2Rs have also been developed – e.g. WIN55-212,2, CP55-940, HU-210 (agonists) and AM251, SR141716A (antagonists) • Most were developed as research compounds to probe the endocannabinoid system – Now notorious as constituents of ‘spice blends’ (‘legal highs’) • Importantly, of the ~100 plant cannabinoids, 3 are known CB1R/CB2R ligands: – D9-THC (tetrahydrocannabinol) • principal psychoactive component • Partial agonist at CB1R and CB2R – CBN (cannabinol) • Agonist • ~50x times less potent than D9-THC – THCV (tetrahydrocannabivarin) • Competitive antagonist at CB1R and CB2R [email protected] 10 All CB1R ligands are not the same… • D9-THC is a partial agonist at CB1 receptors[6] • Partial agonists bind to, but do not fully activate the target receptor. • Not true for most synthetic cannabinoids • Found in ‘spice blends’ and ‘incenses’ • Typically full agonists WIN55-212,2 [email protected] 11 Beyond the endocannabinoid system • The pharmacology of the majority of cannabinoids remains unknown or poorly defined. • Goes well beyond effects mediated by the endocannabinoid system • Cannabidiol (CBD) is typically the second most common plant cannabinoid and so serves as a good example • No evidence of functional CBD interactions with CB1R/endocannabinoid system – can act as a low affinity, high potency CB2R antagonist (i.e. at high micromolar concentrations) but concentrations required would be difficult to achieve in vivo.[5] [email protected] 12 Cannabidiol (CBD) pharmacology • Non-endocannabinoid targets: – GPR55 antagonist (PMID 17876302) – 5HT1A agonist (PMID 16258853) – Adenosine reuptake inhibition – TRPV1 agonism (PMID 16728591) – Bidirectional modulation of intracellular Ca2+ (PMID 19228959) – Allosteric modulator of mu and delta opioid receptors (PMID 16489449) – VGSC blockade (only at high micromolar concs; unpublished) • Caveats: – All are in vitro and have not been definitively linked to functional effects in whole animals/humans. – Some concentrations used are higher than can be reached in brain (functionally implausible). [email protected] 13 Disentangling medicinal from recreational • Debates about recreational use of cannabis often invoke the anecdotal (historical) and modern day evidence base associated with medicinal use. • Significant risks associated with doing so since: – Assertions very often based on very early preclinical evidence. – Many making such assertions have no scientific, let alone medical, training – A single personal experience is often used to substantiate generalisations (‘the miracle of n=1’) – Ancient historical evidence is ascribed greater validity due to its age; logical? – Personal/subjective/individual experience or perceived ‘persecution’ seem to limit broader thinking about populations and society • Let’s have a look at some of the established evidence… [email protected] 14 Historical medicinal use • Written evidence asserting medicinal use predates Christianity. • Majority of claimed effects are likely to be via D9-THC or CBD as other constituents present in very limited quantities. • Western knowledge of cannabis begins in the 19th century where medical claims are made for the following: – Glaucoma – Cramps – Gout – Burns (topically) – Appetite stimulation – Bowel discomfort – Analgesia (pain relief) – Epilepsy – Colic – Insomnia – Diabetes – Complex mental health problems (most likely schizophrenia, depression etc.) Compiled from: [6, 7 & 8] [email protected] Current medicinal use • There are more licensed cannabinoid-based drugs currently available than one might think: Name Content Indication Manufacturer Licence (use) granted Sativex THC/CBD (50:50) Pain and spasticity GW Pharma 2005 Marinol/dronabinol THC Nausea & Solvay 1988 vomiting, pain, appetite stimulation Nabilone Synthetic THC Pain, nausea & Valeant 1985 vomiting Rimonabant CB antagonist Anti- Sanofi-Aventis 2006 obesity/smoking cessation (withdrawn 2008) [email protected] Medicinal use: historical vs present • Interesting comparisons between historical usage and modern day disease targets for cannabinoid therapeutics. Historical Modern (L=licensed) Glaucoma Currently being investigated Appetite stimulation Marinol (L) and others being developed Bowel discomfort, colic Colitis, IBS under investigation Analgesia (pain relief) Sativex (L), Nabilone (L) and others being developed Epilepsy URB597, CBD, CBDV, THC and THCV under investigation Insomnia Under investigation Diabetes THCV? CBD? Complex mental health CBD for schizophrenia problems [email protected] Natural ≠ safe or ‘the myth of herbals’ • >500 separate constituents of cannabis • We don’t know what most of them do in the lab, let alone in people. • We don’t know how many of them might interact with existing medicines or diseases. • Sharks and deadly nightshade are ‘natural’ but you wouldn’t swim with one before eating the other! • Whilst a large historical evidence base