THE PROS AND CONS OF THE USE OF CANNABIS
AS A MEDCINE IN GENERAL PRACTICE:
FROM THE LAB TO THE PATIENT (AND
EVERYTHING IN BETWEEN)
Professor Michelle Glass, Head of Department of Pharmacology and Toxicology, University of Otago
Dr Karen Oldfield, Senior Medical Research Fellow, Medical Research Institute of New Zealand
On behalf of the Medical Cannabis Research Collaborative (NZ)
Disclaimer
This presentation was prepared by the MCRC.
The opinions expressed belong to the individual members of the MCRC and do not reflect the view of the employers, organisations or government agencies to which
they are affiliated.
Not for public dissemination outside of the College of General Practitioners..
The material may not be reproduced or distributed, in whole or in part, without the prior written permission of the MCRC.
Why?
• Misuse of Drugs (Medicinal Cannabis) Amendment
Act 2018
• Mechanism of Action?
• Definitions?
• Evidence for Use?
• Harms?
• Regulations?
• Impact on Health Care Professionals and their
Patients?Photo credited to Andy Palmer at Wikimedia Commons. Licensed for re-use
under CC BY 4.0 International, https://creativecommons.org/licenses/by-sa/4.0,
no changes made
Definitions
Photo by Rick Obst, Licnesed for reuse under CC BY 2.0
https://creativecommons.org/licenses/by/2.0/deed.en, no changes
made.
• Great confusion around what medicinal
cannabis actually is…
• Some people say it isn’t psychoactive i.e.
CBD, some say it is any cannabis used
to treat a medical condition, some say it
is herbal only, whole plant only, others
include pharmaceutical grade products.
• For the purposes of this talk we are
referring to any form of
cannabis/cannabinoid that is used to
treat a medical condition.
• Up to 108 phyto-cannabinoids have
been isolated from the cannabis
plant
• The acids of THC and cannabidiol
are the most prevalent
• Another ~300 chemicals, including
terpenes and flavonoids
Phyto-cannabinoids
Krizek et al (2018) Journal of Cleaner Production 193:391-396
THCA THC
CBDA CBD
https://commons.wikimedia.org/wiki/Cannabis_sativa#/media/File:Cannabis_sativa2.jpg
CB1
Brain
Lungs
Vascular system
Muscles
GI Tract
Reproductive Organs
Immune system
CB2
Spleen
Bones
Immune cells
O
NHOH
ANANDAMIDE THC
CB1 and the Endocannabinoid system in the brain
Lu and Mackie, 2016
https://doi.org/10.1016/j.biopsych.2015.07.028
THC – partial agonist at CB1 and CB2
-12 -10 -8 -6 -4
-100
-50
0
50
100
Eff
ect
Rimonabant
AMB-FUBINACA
AEA
2-AG
THC
agonist
inverse agonist
• >65 discrete molecular targets
• Most implausible (low affinity)
• Unlikely to be through endocannabinoid system
Blurred lines
Separation of ‘Medical’ and ‘Recreational’ Use..and
Canadian cannabis cultivar analysis
(Medicinal use)
Moderate THC, no CBDHigh THC, no CBD
low THC, low CBD
Very low THC, high CBD
Heterogeneity of Delivery =
Wide Variance in Bioavailability
Blausen.com staff (2014). "Medical gallery of Blausen Medical 2014". WikiJournal of
Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN2002-4436.
CC BY 3.0 https://creativecommons.org/licenses/by/3.0/deed.en, no changes made.
There are multitudes of ways that patients can access
cannabinoid products overseas- leads to difficulties in
gauging onset of effects, adverse reactions and efficacy.
Pharmacokinetics of different delivery25mg THC Dose (in whole cannabis preparation)
0
10
20
30
40
50
60
70
80
90
100
-1
0.1
6
0.5 1
1.5 2 3 4 5 6 8
Dru
g E
ffect
Hours post dosing
0
2
4
6
8
10
12
14
16
BL
0.1
6
0.5 1
1.5 2 3 4 5 6 8
Blo
od
TH
C (
ng
/m
L)
Hours post dosing
Smoke
Vape
Oral
Data generously provided by Ryan Vandrey – John Hopkins University, School of Medicine
0
1
2
3
4
5
BL
0.1
6
0.5 1
1.5 2 3 4 5 6 8
Blo
od
11-
OH
-TH
C (
ng
/m
L)
Hours post dosing
Evidence in support- THC alone or THC/CBD
• National Academies of Sciences, Engineering, and Medicine report 2017:
• Modest therapeutic effects noted:
• Chemotherapy Induced Nausea and Vomiting- oral cannabinoids- effective anti-emetics
• Chronic pain (primarily neuropathic)- cannabis or cannabinoids- more likely to experience a
clinically significant reduction in pain when compared with placebo
• Spasticity in Multiple Sclerosis- oral cannabinoids-short term use improves patient related
spasticity symptoms
A bit more on chronic pain
• 2015 meta analysis (Whiting et al, 2015)
• Associated with least a 30% reduction in pain (37% vs 31%, OR, 1.41 [95% CI, 0.99-2.00], overall reduction in Numerical Rating Score (0-10 scale) ; WMD−0.46 [95% CI, −0.80 to −0.11]
• 2018 systematic review, non cancer chronic pain (Stockings et al, 2018)
• All RCT – at least 30% reduction in pain (OR 1.31 (1.02 to 1.69) 29% in treated, 25.9% in placebo. Overall reduction in Numerical Rating Score (0-10 scale) -0.14 (-0.20 to -0.08). Number needed to treat benefit 24. Number needed to harm 6 (all cause adverse events), 40 – study withdrawal due to adverse event.
Evidence in support- CBD alone
• Strongest evidence is as adjunct therapy in Refractory Childhood Epilepsy
Syndromes (~20mg/kg/day)
• Dravet Syndrome, Lennox-Gastaut Syndrome
• Limited evidence in social anxiety- single doses
• Limited evidence as an adjunct to addressing positive symptoms in
schizophrenia
Bassir et al, Cannabidiol as Adjunctive Treatment for Schizophrenia 2019 Psychiatric Times 36:4
No or Insufficient Evidence to support/refute the
use of cannabis as an effective treatment
• Cancers
• Cancer associated anorexia cachexia/anorexia
• Symptoms of IBS
• Epilepsy (excluding refractory childhood epilepsy syndromes)
• Spasticity due to spinal cord injury
• AMLS symptoms
• Chorea and symptoms associated with Huntington’s disease
• Motor system symptoms associated with Parkinson’s disease
• Dystonia
• Abstinence in the use of addictive substances
• Mental Health outcomes
Some Guidelines and Position statements on
the Use of Cannabis as a Medicine- home and
away
Image credited to TUBS via Wikimedia Commons, CC BY 3.0 Unported licence https://creativecommons.org/licenses/by-sa/3.0/deed.en, no
changes made.
NZMA Position and Recommendation on Medicinal
Cannabis (Nov 2017)https://www.nzma.org.nz/__data/assets/pdf_file/0009/77958/Medicinal-cannabis-position-Statement_November-2017.pdf
Faculty of Pain Medicine- ANZCA
• NNTB: 24 patients (95% CI 15 to
61)
• NNTH: 6 patients (95% CI 5 to 8)
http://fpm.anzca.edu.au/documents/pm10-2018.pdf
Medical Cannabinoids Summary Guideline from The College of Family Physicians of Canada
https://www.cfpc.ca/uploadedFiles/CPD/Cannabinoid_Guidelines_One-Pager.pdf
Benefit summary of cannabinoids vs placebo from
The College of Family Physicians of Canada
https://www.cfpc.ca/uploadedFiles/CPD/Cannabinoid_Guidelines_One-Pager.pdf
Neuropathic Pain: Pharmacotherapy Treatment
Outcome: Meaningful (30%) Pain Improvementhttps://www.cfpc.ca/uploadedFiles/CPD/Cannabinoid_Guidelines_One-Pager.pdf
Adjunct
Observed Adverse Effects
• CBD only
• Metabolised by cytochrome p450-potential for drug interactions
• Change in liver function tests (during use with anti-epileptics)
• Diarrhoea
• Fatigue/tiredness
• Appetite/weight changes
• THC preparations (Most common)
• Drowsiness/fatigue
• Dizziness
• Dry mouth
• Cough (if smoked)
• Anxiety
• Nausea
• Cognitive effects
Risks to person
• If smoked, respiratory issues results in chronic cough and phlegm
production
• Impairment in cognitive domains of learning, memory and attention- limited
evidence for whether or not this is a long term effect
• Greater frequency of cannabis use increase likelihood of developing a CUD
• Psychosis – particularly at high THC
Blurred lines 2
Image credited to eggrole.wordpress.com, licensed under CC GA 2.0,
https://creativecommons.org/licenses/by/2.0/, no changes made
Image from Vaping360, vaping360.com/cbd-oil-cannabidiol-hemp-oil/. , licensed
under CC GA 2.0 https://creativecommons.org/licenses/by/2.0/, no changes
made
L K U H J G C V R A N N B A S B U S J L O G J U S W
S G L N E N D O C A N N A B I N O I D E N W X T Y D
A L M P E S P A R T N Q B N X D E L Y H E P I D S X
S T E N M X Y W S P A E P I V N A U D E S O D W T A
WS N M E T Y S A P L U J N T H N U S O P L E S V T
N P M K L O C S W A T I V E E D S G J L T Y L P L W
L A B I B L E R T Y N A U P L W S A T J U M T S P Y
E S L U N F P R C A N N B I S N N D E R J O A H J N
X T K C A F N N E B I S H L J K J S M O K I N G R D
N I L O O H J N M M S D R E Y K S A R P L K I J U N
A C A N N T C B I S K L J P P O L J G T D B N R F Y
S I W A S N A U S O P G U S W Y H H I O P L E L O C
I T K I L S N F T G U J X W C R H P L O N F T F H X
L Y W A K M N C E P I J N U F C V A L H H Y E L O N
U D D U H N A K O A Y P U C N N I L P V A C T L J C
X L K X F U B K D R O N A B I N O L N M J X H B S W
R L K N U F I U N K P W I P L N F I D C W A C S T I
S W Y J O C D P L C V X J K X C A A N N I S D O L L
P M A S A T I V E X P L F R T S E T W R Y U I O J W
A G S E Q W O I G E R T R T T Z X I S A S E E T J E
R N Q W G H L K L Z S I P O S X T V Q A U Y E F W D
H S E R T Y Q W E A S T I C I T Y E R T Q S E T S I
C P E R T Y U I Q W E T S E P I D I O L E X W S I B
I E W E R T Y H U J W S D R G H I P O E H S P Q T L
T Y N A U S E A S D F A N N A U H R D F R J N E F E
Y B W D F G Q A S W P U V D T W E S R C T E R T T Y
CANNABIS
DELTA-NINE-THC
SATIVEX
CANNABIDIOL
EPIDIOLEX
ENDOCANNABINOID
SPASTICITY
NAUSEA
PALLIATIVE
EDIBLE
SMOKING
DRONABINOL
New Zealand Regulatory Update
Crossing international borders with cannabis is illegal. Government of Canada / Gouvernement du Canada. Original image attributed to dcflyer, cropped by Moxy at Wikimedia Commons. CC BY-SA 4.0 , https://creativecommons.org/licenses/by-sa/4.0/deed.en
• Exception and statutory defence for possession and use of cannabis for people
requiring palliation who have a recommendation from a registered health professional
• De-scheduled CBD: no longer a controlled drug (prescription drug only)
• Allow the use of locally sourced plants, fruits and seeds
• Ability for regulator to set quality standards for processes and products
• Requirements for medicinal cannabis regulations to be made by 18 December 2019
• Establishment of a licensing regime
• Set up of the Medicinal Cannabis Agency
Misuse of Drugs (Medicinal Cannabis) Amendment
Act 2018
• Proposes control of supply chain activities through licensing regime
(cultivation, manufacture and supply)
• Proposes patient access through prescription
• Agency to be established within the MOH
Proposed Medicinal Cannabis Scheme
• Consultation Period Now Open
• Due by 5pm, Wednesday 7 August 2019
• Information sessions Auckland, Wellington and Christchurch (July 22 to Aug 1)
• Stakeholder groups (industry, Maori industry, medical professionals and consumers)
• Medicinal Cannabis Advisory Group (MCAG) meeting in early September to review
responses to regulatory proposals
• Cabinet approval to draft regulations – October
• Cabinet approval of regulations - December
Proposed Medicinal Cannabis Scheme
• Objective: To improve access to affordable quality medicinal cannabis
products
• Increase supply of products
• Commercial cultivation of cannabis in NZ
• Manufacture of medicinal cannabis products in NZ
• Local and imported products to meet the same minimum quality standards
Proposed Medicinal Cannabis Scheme
• Objective: To improve access to affordable quality medicinal cannabis
products
• Improving access for patients
• Products made to quality standards
• Guidance on prescription
• Clearer information on what products are available
Proposed Medicinal Cannabis Scheme
• Quality Standards – why do we need them?
• Patient protection
• If there are no requirements for quality standards, then:
• Poor or unknown quality of products
• Unknown consistency of cannabinoids
• Possible contamination (pesticides, heavy metals, mould etc.)
Proposed Medicinal Cannabis Scheme
• Quality Standards for Manufacture
• Current approach for manufacture of all other medicines available under prescription:
• NZ code of Good Manufacturing Practices (GMP)
• Ensures that products are manufactured consistently, are reliable and of appropriate quality
• This model is based on the internationally recognised GMP quality system
• MOH is seeking advice on quality standards for cultivation, manufacturing
and finished products.
Proposed Medicinal Cannabis Scheme
• Quality Standards for Manufacture Options in the Consultation Document:
• GMP versus GPP
• Establish a less rigorous standard that the Canadians implemented (GPP) for non-prescription fresh, dried and cannabis oil products only.
• NZ not intended to have non-prescription products available.
• Existing GMP audit/validation processes already in play.
• Compliance to NZ Product Quality monograph / specification.
• Applies to starting material / API and finished product
• Finished product to also comply with:
• dose form, shelf-life, packaging and labelling requirements
• Certificates of Analysis generated to provide evidence that the product meets the standard
• What other product data would you want to see available?
Proposed Medicinal Cannabis Scheme
• Proposed Finished Dosage Forms under the Scheme
• Products for smoking will not be permitted (but products for vaping will)
• Modified release dose and medicines required to be sterile only allowed if
approved/provisionally approved by the MOH.
• Food containing medicinal cannabis not permitted under the Food Act 2014- no edible
products.
• Cannabis-based dietary supplements, natural health products and nutraceuticals must meet
the requirements of the Scheme
Proposed Medicinal Cannabis Scheme
Current Prescribing Considerations- THC
• Sativex-
• Only Medsafe approved medications licenced in NZ.
• Not PHARMAC funded. Approved for MS Spasticity adjunct treatment only.
• All other THC preparations and unapproved therapeutic Sativex requests
require subsequent Ministerial Approval prior for prescription
• More stringent guidelines for non-pharmaceutical grade products
• Regulation 22 of the Misuse of Drugs Regulations 1977
https://www.health.govt.nz/our-work/regulation-health-and-disability-system/medicines-control/medicinal-cannabis/prescribing-medicinal-cannabis-products
Current Prescribing Considerations- CBD
• All authorised prescribers can prescribe, not a controlled drug.
• No CBD products currently have consent for distribution in NZ, however
unapproved products can be prescribed by a medical practitioner.
• >2% THC of the total cannabinoid content = Controlled drug.
• Many “CBD” preparations seen online fall under this and cannot be imported.
https://www.health.govt.nz/our-work/regulation-health-and-disability-system/medicines-control/medicinal-cannabis/cbd-products
Other Prescribing Considerations
• Section 25 of the Medicines Act permits use of unapproved medicines when
following Rights 4 (Service of appropriate standard), 6 and 7 of the Code of
Health and Disability Services Consumers’ Rights
• Written consent required if for an experimental use of a medicine.
• Experimental = little or equivocal documented support of use
https://www.medsafe.govt.nz/profs/RIss/unapp.asp
• Prescribing Requirements under the Scheme (unchanged):
• Approved (including provisionally) CBD products can be prescribed by medical practitioner
or nurse practitioner
• Unapproved CBD products can be prescribed by medical practitioner
• Unapproved (non-CBD) products that do not meet the quality standards continue to be
prescribed with MOH approval
Proposed Medicinal Cannabis Scheme
• Prescribing Requirements under the Scheme – proposed changes
• Approved (non-CBD) products, e.g. Sativex:
• On-label use: can be prescribed by medical practitioners; remove the requirement for specialist
recommendation
• Off use: can be prescribed by medical practitioners; remove the requirement for MOH approval but
specialist recommendation still required
• Unapproved (non-CBD) products that meet the quality standards
• Can be prescribed by specialists, remove the requirement for MOH approval
• Add provision for medical practitioners to prescribe with specialist recommendation.
Proposed Medicinal Cannabis Scheme
Doctor-Patient Relationship
• GPs are the best placed to discuss the use of cannabis as a medicine with
their patients
• Patients have access to millions of websites that suggest the use of cannabis
or CBD for various conditions that may not be supported by rigorous trials
• Quality of products is not assured unless pharmaceutical grade
• Informed consent essential if deciding to prescribe.
• Concerns around pressure to prescribe?
Examples of Colorado Experiences with the Use of
Cannabis as a MedicineFrom Caplan, G. Medical Marijuana: A Study of Unintended Consequences 43 McGeorge Law Review 127 (2012)
• January 2009- 6369 registrants to March 2011- 127,816 registrants
• 70% of doctors recommendations were written by fewer than 15
physicians in the state.
• Severe or Chronic Pain accounted for 94% of all reported conditions.
• 61% Medical Cannabis patients are male with an average age of 39
years
Discount Medical Marijuana cannabis shop at 970 Lincoln Street, Denver, Colorado, © O'Dea at Wikimedia Commons, CC
BY-SA 4.0, https://creativecommons.org/licenses/by-sa/4.0/deed.en., no changes made.
Take home thoughts courtesy of
Associate Professor Giles Newton-Howes (Consultant Psychiatrist and Member of the MCRC)
• THC is probably not good, and may even be bad.
• CBD is probably good and may in fact be really useful.
• Using any cannabis product as a child/adolescent/young adult (under 25) is
bad, the younger they are, the more bad it is.
• The evidence currently is weak. So prescribers have lots of responsibility!
Reminder: Up for consultationhttps://www.health.govt.nz/publication/medicinal-cannabis-scheme-consultation
Consultation closes 5pm, 7 August, 2019
Key questions
How to achieve equity of access to potential economic benefits
of entering industry?
What product quality standards would you require to prescribe?
What level of oversight would you want in a prescribing
decision (none, peer review, specialist recommendation)?
Would you expect unapproved medicinal cannabis products to
have undergone any clinical trials?
Feel free to contact Tara Creaven-Capasso if any
questions specific to this regulatory update:
Members of the Medical Cannabis Research
Collaborative
Prof Michelle Glass, Head of Department of Pharmacology and Toxicology, University of Otago, Dunedin
Dr Karen Oldfield, Senior Research Fellow, Medical Research Institute of New Zealand
Dr Alex Semprini, Deputy Director, Medical Research Institute of New Zealand
Dr Irene Braithwaite, Deputy Director, Medical Research Institute of New Zealand
Associate Professor Giles Newton-Howes, Department of Psychological Medicine, University of Otago, Wellington
Professor Richard Beasley, Director, Medical Research Institute of New Zealand
Dr Mary-Jane McCarthy, Manager of Forensic Toxicology and Pharmaceuticals, Institute of Environmental Science and Research Ltd
Mrs Tara Creaven-Capasso, Director, Caduceus Medical Development
Ms Deborah Tod, Business Manager, Sustainable Production, Plant and Food Research
Mr Stuart Larsen, NZ Biotron Manager, Lincoln University
Mr Jordan Tewhaiti-Smith, Research Fellow, Medical Research Institute of New Zealand
