Weeding out the myths on Medical Cannabis

Weeding out the myths on Medical Cannabis Presented by A/Prof David Allsop Lambert Initiative for Cannabinoid Therapeutics University of Sydney For Walk on the Wild Side 2016: Superstition or Evidence? Brisbane The University of Sydney Page 1

Medical Cannabis - The myths Myth # 1. Medical cannabis is illegal in Australia Myth # 2. All cannabis is good for you (Straw man) Myth # 3. The evidence for medical cannabis is in the studies have been done The University of Sydney Page 2

Myth # 1. Medical cannabis is illegal in Australia The University of Sydney Page 3

Prohibited Substance The University of Sydney Page 4

Cannabis hasn t always been illegal Pfizer 1929 (Parke-Davis) The University of Sydney Page 5

Cannabis prohibition The University of Sydney Page 6

Restrictions on the manufacture, movement and use of narcotic drugs cannabis (THC) = Schedule 9 The University of Sydney Page 7

Prohibited Substance The University of Sydney Page 8

Legal medical cannabis when separately specified in schedules Sativex (THC+CBD) is Schedule 8 Cannabidiol (CBD) is Schedule 4 Dronabinol and Nabilone (THC) Schedule 8 The University of Sydney Page 9

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Special Access Scheme - TGA Specialist doctor applies to the TGA to import drugs on behalf of a patient The TGA s assessment balances a number of factors, including: (1)The patient s doctor must be able to justify using the product, demonstrating the seriousness of the patient s condition and the history of other treatments. (2) Information about the route of administration, dose, active ingredients, proposed monitoring procedures, and any data on the safety and efficacy of the product. (3) The prescriber must have the relevant expertise appropriate to the condition being treated. The University of Sydney Page 11

Special Access Scheme - TGA - State based laws have been at odds with TGA allowance of Schedule 9 drugs, but individual states, including QLD, have recently adapted to facilitate The University of Sydney Page 12

Any schedule of drug can be used in a clinical trial, including cannabis plant matter - Drug must meet minimum quality standards (e.g. GMP certified) - Drug and trial must be approved by an authorized ethics committee The University of Sydney Page 13

Pharmaceutical THC vs. vaporised botanical leaf cannabis for cachexia (wasting disorder) in palliative care (NSW government funded clinical trial) AIM: Vaporised high THC botanical leaf matter in stimulating appetite in a palliative care population. The University of Sydney Page 14

Now the federal government are making production and manufacture legal in Australia The University of Sydney Page 15

And the states are scrambling to bring their own laws into line 2017 onwards will see home grown cannabis medicines in Australia The University of Sydney Page 16

Finally, the TGA are in the process of moving cannabis out of the S9 poisons category, into S8 The University of Sydney Page 17

Myth # 1. Medical cannabis is illegal in Australia SORT OF! The University of Sydney Page 18

Myth #2. All Cannabis is good for you "God said, 'Behold, I have given you every herb bearing seed... And the earth brought forth grass and herb yielding seed after its kind. The University of Sydney Page 19

Myth #2. All Cannabis is good for you The University of Sydney Page 20

Last 12 month drug use (1991-2010) National Drug Strategy Household Survey % Cannabis is consistently the most prevalent illicit drug used in Australia The University of Sydney Page 21

Number of treatment episodes 2008/2009 Report on the National Minimum Data Set Number of treatment episodes 2 nd most prevalent reason for presentations to AOD services in Australia The University of Sydney Page 22

Research $ for cannabis is bad The University of Sydney Page 23

Cannabis Harms New England Journal of Medicine 2014 The University of Sydney Page 24

High THC levels in Australian Street Cannabis Swift W, Wong A, Li KM, Arnold JC, et al. (2013) Analysis of Cannabis Seizures in NSW, Australia: Cannabis Potency and Cannabinoid Profile. PLoS ONE 8(7): e70052. doi:10.1371/journal.pone.0070052 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0070052 The University of Sydney Page 25

Cannabis Dependence ALL OTHER CANNABIS USERS 90% DEPENDENT 10%* *Hall, W., & Pacula, R.L. (2003). Cannabis use and dependence: Public health and public policy. Cambridge: Cambridge University Press. The University of Sydney Page 26

Profile of cannabis withdrawal The University of Sydney Page 27

Cannabinoid Replacement Therapy Inpatient cannabis withdrawal Allsop et al (2015) JAMA Psychiatry The University of Sydney Page 28

Suppression of Cannabis Withdrawal. The University of Sydney Page 29

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Myth #2. All Cannabis is good for you "God said, 'Behold, I have given you every herb bearing seed... And the earth brought forth grass and herb yielding seed after its kind. The University of Sydney Page 31

Myth # 3. The evidence for medical cannabis is in the studies have been done The University of Sydney Page 32

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Cannabinoids ever given in purified form to humans in scientific studies (estimate) Abbreviation Full name THC Δ9-Tetrahydrocannabinol THCA Δ9-Tetrahydrocannabinolic acid THCV Δ9-Tetrahydrocannabivarin THCVA Δ9-Tetrahydrocannabivarin acid CBD Cannabidiol CBDA Cannabidiolic acid CBDV Cannabidivarin CBDVA Cannabidivarin acid CBG Cannabigerol CBGA Cannabigerolic acid CBGV Cannabigerovarin CBGVA Cannabigerovarinic acid Abbreviation Full name CBC Cannabichromene CBCA Cannabichromenic acid CBCV Cannabichromevarin CBCVA Cannabichromevarinic acid CBN Cannabinol CBNA Cannabinolic acid CBNV Cannabinovarin CBNVA Cannabinovarin acid CBL Cannabicyclol CBLA Cannabicyclolic acid CBV Cannabivarin The University of Sydney Page 34

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Quality of the evidence - Risk of bias? - Was it double blind, single blind, open label? - Was it randomised appropriately? - What was the sample size? - Was the main outcome measure specified clearly a priori? Or were findings fished for? - How many studies contribute to that evidence base? - Are there enough good quality studies to do a meta analysis The University of Sydney Page 38

State of the evidence The University of Sydney Page 39

State of the evidence - Whiting et al JAMA June 2015 Illness Reduction in Pain # of Studies # of patients Findings 28 (8) 590 37 % on cannabis vs 31% on placebo Spasticity in MS 14 2280-0.36 reduction (on a 6 point scale) Nausea and Vomiting 28 (3)? OR 3.82 complete response Strength of Evidence Just significant; Moderate Just significant; Moderate Mixed results; Low Weight + in HIV 4 255 THC > placebo Not significant; Low Depression 5 (0)? Cannabis = placebo Secondary outcomes; Low Anxiety 1 8 CBD > placebo Significant; Low Sleep disorders 2 54 THC > placebo Significant; Low Tourettes 2 36 THC > placebo Significant; Low Glaucoma 1 6 Cannabis = placebo Not significant; Low Psychosis 2 71 CBD = placebo & amisulpride Not significant; Low The University of Sydney Page 40

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What about epilepsy? 2012 4 studies, total of 30 patients (8 in each), mixed results, very low quality evidence 2014 American Academy of Neurologists available evidence is insufficient to draw conclusions about the safety and efficacy of cannabinoids in the treatment of epilepsy The University of Sydney Page 42

What about epilepsy? The University of Sydney Page 43

Myth # 3. The evidence for medical cannabis is in the studies have been done The University of Sydney Page 44

Australia is stepping up to address the Cannabis Evidence Gap The University of Sydney Page 45

The Lambert Initiative for Cannabinoid Therapeutics Lambert Initiative University of Sydney NSW, Australia 2006 The University of Sydney Page 46

Major aim To explore the potential of and to develop novel cannabinoidbased therapies for the treatment of: Epilepsy Pain Cancer Dementia Mental illness/addictions Obesity/diabetes/metabolic disorders The University of Sydney Page 47

Areas of development -from farm to pharma- Sourcing and extracting cannabinoids Medicinal chemistry Cellular screens Preclinical animal models Early human (phase 1) trials Human psychopharmacology Larger clinical trials The University of Sydney Page 48

Unlocking the medicinal potential of the cannabis plant The University of Sydney Page 49

o o o Over 100 cannabinoids in the plant, many of which are non-psychoactive. Each cannabinoid has its own therapeutic potential This includes terpenoids, flavonoids, and ensemble and entourage effects The University of Sydney Page 50

Sourcing cannabinoids The University of Sydney Page 51

Cannabinoid sourcing Plant genetics R&D Extraction Ecofibre Ecofibre ihemp CBD CBDA CBDV CBDVA CBC CBCA CBN THCA THCV THCVA Biomedical R&D GMP production The University of Sydney Page 52

Preclinical research The University of Sydney Page 53

Preclinical vision (epilepsy example) *Phytocannabinoids Screening against epilepsy-relevant targets FLIPR (Connor) TEVC (Collins) Dynamin (Robinson) NIH Psychoactive Drug Screen Patch clamping electrophysiology *+ tweaked versions + combinations + terpenes Animal models that express epilepsy-relevant channelopathies Back translation The University of Sydney Page 54

Areas of development Sourcing and extracting cannabinoids Medicinal chemistry Cellular screens Preclinical animal models Early human (phase 1) trials Human psychopharmacology Larger clinical trials The University of Sydney Page 55

Areas of development Sourcing and extracting cannabinoids Medicinal chemistry Cellular screens Preclinical animal models Early human (phase 1) trials Human psychopharmacology Larger clinical trials The University of Sydney Page 56

Areas of development Sourcing and extracting cannabinoids Medicinal chemistry Cellular screens Preclinical animal models Early human (phase 1) trials Human psychopharmacology Larger clinical trials The University of Sydney Page 57

Cannabidivarin (CBDV) for paediatric epilepsy (NSW government funded clinical trial) AIM: To test the efficacy of CBDV in treating seizures in children with epilepsy. The University of Sydney Page 58 Team: I. McGregor, D. Allsop, N. Lintzeris, Sydney Children s Hospital Network, GW Pharmaceuticals

Randomised control trial using oral THC/CBD extract to treat chemotherapy induced nausea and vomiting (CINV) (NSW government funded clinical trial) AIM: To examine the safety and efficacy of orally administered THC/CBD extract as ancillary medication to standard treatment in CINV. The University of Sydney Page 59

Remain nimble in a shifting landscape Amendment to Narcotics Act 1964 Will enable licenses for cultivation and manufacture of cannabis for therapeutic use Rescheduling from Schedule 9 to 8 To overcome current laws that make all cannabis (even as a medicine) a prohibited substance State based legislative frameworks emerging to enable compassionate use Different approaches by different states but expect increased use in coming 1-4 years The University of Sydney Page 60

Medicinal cannabinoid use for childhood epilepsy in the Australian community PELICAN AIM: To document the types and patterns of cannabinoid use for the treatment of childhood epilepsy in Australia. Face-to-face semi-structured interview Collection of sample of cannabinoid product Chemical analysis of cannabinoid product The University of Sydney Page 61 Team: A. Suraev, N. Lintzeris, D. Allsop, J. Arnold, J. Stuart, I. McGregor.

The usual research cycle The University of Sydney Page 62

PELICAN The University of Sydney Page 63