Healthcare Professional Guide · As of Feb 2020, the TGA had approved medicinal cannabis for the treatment ... prescription of medicinal cannabis in one or more of the following country

for Medicinal Cannabis

Healthcare Professional Guide

Clinical guidance documents

Medicinal cannabis (also called medical marijuana) refers to the use of the cannabis plant and its component cannabinoids (such as THC and CBD) as a medical treatment for certain conditions and their associated symptoms. The flowering head of the cannabis plant contains the highest concentration of cannabinoids, differing to hemp oil which, in Australia comes from pressing the seeds of hemp plants.

It should be noted that referring to cannabis as though it were one type of medicine is misleading as there are various forms that medicinal cannabis can take as well as a range of strengths and varieties.

Cannabis has been used medicinally since 1000 BC, initially as an anaesthetic and was introduced from India to Europe around the mid-19th century1. It was used for a variety of conditions including rheumatism, convulsions, and muscular spasms.1,2 In the early 1900’s, although medicinal cannabis was widely used, chemists were unable to create a consistent product because the active ingredients were unknown. By the mid-20th century, cannabis became illegal in most

countries around the world and its usage by the medical community ceased. In 1965, Raphael Mechoulam and Yehiel Gaoni isolated THC for the first time which led to a flurry of investigations. Twenty five years later Mechoulam discovered endogenous cannabinoids as well as the endocannabinoid system, which again reignited interest and research into the plant3.

The last twenty years has seen a gradual, world-wide re-adoption of cannabis for medical purposes. It has been legalised in Australia, Canada, Israel, the United Kingdom, many US States, as well as several European countries including but not limited to Germany, Italy, the Netherlands and Finland.

In the last 45 years, there have been nearly 600 studies conducted using medicinal cannabis, with more than a third of those studies published in the last five years. This renewed global interest in medicinal cannabis has led to a better understanding of the cannabis plant and identification of many more active components that have potential benefits across a range of symptoms.

Medicinal CannabisA Brief Overview

01

20

22

26

MEDICINAL CANNABIS OVERVIEW

METHODS OF ADMINISTRATION

DOSING

PATIENT SUITABILITY & TREATMENT PLAN

02 POTENTIAL THERAPEUTIC USES

06 ACCESS TO MEDICINAL CANNABIS IN AUSTRALIA

10 HOW MEDICINAL CANNABIS WORKS

12 CANNABINOIDS EXPLAINED

16 POTENTIAL OPIOID-SPARING EFFECTS

28 REFERENCES

1Little Green Pharma

POTENTIAL THERAPEUTIC USES

Potential therapeutic uses

EPILEPSY

CANCER PAINCHRONIC PAIN

NEURODEGENERATIVE

SPASICITY IN MULTIPLE SCLEROSIS

CHEMOTHERAPY INDUCED NAUSEA AND VOMITING

Potential clinical applications

The scientific evidence supporting the use of medicinal cannabis is listed in the TGA’s Guidance for the Use of Medicinal Cannabis in Australia Overview4. It is important to note that the TGA has advised that they will look at each application on its merits and does not have a dedicated list of indications or excluded conditions. There are specific guidance documents, based on clinical evidence, available for the following conditions:

Who may benefit from Medicinal Cannabis?


• Chronic Non-Cancer Pain

• Palliative Care

• Epilepsy

• Chemo-Induced Nausea and Vomiting (CINV)

• Multiple Sclerosis

There is also a growing body of evidence supporting the use of medicinal cannabis in the following conditions:

• Anxiety 5,6

• Arthritis 7,8

• Cachexia 9-12

• Cancer, related nausea, pain, appetite loss, anorexia and debilitation 12-14

• Gilles de la Tourette syndrome 15,16

• Glaucoma 17

• Irritable Bowel Syndrome 18-20

• Parkinsons Disease 21-23

• PTSD 24,25

• Sleep Disorders 26,27

Please note:The TGA has advised the medical conditions for which it will allow access to medicinal cannabis is not limited to specific conditions and notes it is the responsibility of the prescriber to determine whether the specific product is suitable for the condition being treated based on clinical evidence’4. As of Feb 2020, the TGA had approved medicinal cannabis for the treatment of 130+ conditions.28

Source: Australian Government Department of Health, Submission to the Senate Community Affairs References Committee, Senate inquiry into the current barriers to patient access to medicinal cannabis in Australia, January 2020.

Indications (as at 31 Dec 2019) (Total SAS B approvals by indication)

18,000

16,000

14,000

12,000

10,000

8,000

6,000

4,000

2,000

0

Pain

Canc

er R

elat

ed

Sym

ptom

s

Psyc

holo

gica

l

Epile

psy

/Sei

zure

Mov

emen

t Dis

orde

rs

Slee

p

SAS

B ap

plic

atio

n ap

prov

als

11% 2,852

71% 17,969 PAIN

9% 2,287 4%

9843% 796

2% 387

Chronic Pain (undefined) 15,638

Other (Fibromyalgia, Migraine, IBD) 323

Neuropathic pain 2,008

2 3Healthcare Professional Guide for Medicinal Cannabis Little Green Pharma

Chronic pain, epilepsy, neurodegeneration, spasticity in multiple sclerosis, cancer pain and chemo-induced nausea and vomiting are some of the conditions listed as potential therapeutic uses of, or indications for, the prescription of medicinal cannabis in one or more of the following country health care professional guidelines:

In November 2016, Australia legalised cannabis for medical purposes, at the same time allowing for Australian cultivation of the plant. The Therapeutic Good Administration (TGA) requires strict testing and certification of both medicinal cannabis plants and finished products under Therapeutic Goods Act Order No. 93. This order ensures all medicinal cannabis products produced in, and imported into Australia, meet strict standards governing harmful pesticides, moulds, foreign matter and other contaminants and adulterations.

The TGA’s current position is cannabinoid therapy should only be considered after established treatments have been trailed and patients are refractory or unable to take due to adverse events or unwanted side effects. The exception is palliative care. As supporting evidence for the use of cannabinoid products develops through robust clinical trials, the TGA is expected to update its guidelines and expand the clinical settings to include conditions for which medicinal cannabis has been adequately researched or has robust data.

The foremost difference between street cannabis and medicinal cannabis is quality control. As the street cannabis market is, by definition ‘illegal’, regulatory bodies do not impose standards or testing requirements. In contrast, medicinal cannabis in Australia is highly regulated to ensure patient safety and consistency of product formulation.

A number of safety concerns result from the lack of quality control of street cannabis. Without complete chemical analysis in a certified laboratory, the composition of street cannabis is essentially unknown.32-33Concentrations of the psychoactive element, THC (tetrahydrocannabinol), may be significantly higher than expected; increasing risk of adverse events. In addition, contamination of street cannabis with microbes, pesticides, moulds and harmful diluents cannot be ruled out.

MEDICINAL CANNABIS IN AUSTRALIA: OVERVIEW

MEDICINAL CANNABIS: NOT A FIRST LINE TREATMENT

MEDICINAL CANNABIS VS ILLICIT (STREET) CANNABIS

COUNTRY YEAR MEDICAL CANNABIS LEGALISED GUIDELINE


MEDICINAL CANNABIS — GLOBALLY MEDICINAL CANNABIS IN AUSTRALIA

Health Canada Cannabis Guidelines29:https://www.canada.ca/en/health-canada/services/drugs-medication/cannabis/information- medical-practitioners/information-health-care-professionals-cannabis-cannabinoids.html

Israel Ministry of Health Cannabis Guidelines30:https://www.xn--4dbcyzi5a.com/en/2018/01/medical-cannabis-official-israeli-clinical-guide/

The Office of Medical Cannabis31:http://www.ncsm.nl/english/information-for-patients/when-to-use-it-indications

National Institute for Health and Care Excellence70:https://www.nice.org.uk/guidance/ng144/chapter/Recommendations

NZ ministry of health71:https://www.health.govt.nz/our-work/regulation-health-and-disability-system/medicinal- cannabis-agency/medicinal-cannabis-agency-information-health-professionals

THE NETHERLANDS 2003 The Office of Medical Cannabis (NCMS: Nederlandse Associatie voor legale Cannabis en haar Stoffen als Medicatie); NCMS: Indications for medicinal cannabis use 31

ISRAEL 1994 Israeli Ministry of Health; The Green Book: The Official Guide to Clinical Care in Medical Cannabis 30

CANADA 2001 Information for Health Care Professionals: Cannabis (marihuana, marijuana) and the cannabinoids (Health Canada, 2013)29

UNITED KINGDOM 2018 National Institute for Health and Care Excellence; NICE guideline [NG144] Cannabis-based medicinal products (2019).70

NEW ZEALAND 2018 Ministry of Health; Medicinal Cannabis Agency - Information for health professionals.71


CRITERIA FOR PRESCRIBING (VALID AT JUNE 2020):

CURRENT MEDICATION INADEQUATE

Patients must have either tried and be unable to take standard medications for their condition due to intolerance or unsatisfactory side effects profile, or have refused or experienced a lack of response to standard treatments.

CLINICAL EXPERTISE

The clinician submitting the application must be able to show expertise or relevant experience for the condition in which they are prescribing medicinal cannabis, or alternatively have support from a specialist with specific expertise in treating the patient’s condition.

SUPPORTING EVIDENCE

Submission of clinical evidence (e.g. paper or trial showing benefit in the condition being treated) is sometimes required to support an SAS application for medicinal cannabis to treat a particular condition. Support with clinical evidence is available, please contact 1300 118 840 for assistance.

ACCESSING MEDICINAL CANNABIS IN AUSTRALIA

Accessing Medicinal Cannabis in Australia

Medicinal cannabis is available as a treatment option through the TGA’s Special Access Scheme (SAS). As of June 2020, over 46,000 applications for medicinal cannabis have been approved in Australia via the SAS B pathway. All States and Territories have simplified the application process for medical cannabis with the exception of Tasmania. SAS B applications can be completed online and accessed via https://sas.tga.gov.au/. If you practice in Tasmania please check with Department of Health & Human Services Tasmania for the application process.

The first step is to discuss medicinal cannabis your patient to determine whether this treatment is right for them and if they can afford it.

Depending on your location and whether or not the patient is under the supervision of a specialist, you may need to either inform or get approval for prescribing medicinal cannabis from a specialist with expertise in the patient’s condition.

If you believe medicinal cannabis is appropriate, you will need to:

• Ensure there is research to support medicinal cannabis use in the condition*

• Identify an appropriate medicinal cannabis product based on the ratio of THC and CBD used in the research

• Make appropriate applications for approval to prescribe including clinical justification, outline rationale and treatment plan

• Advise how you intend on monitoring the patient

* The TGA has the most commonly prescribed indications listed in the ‘product selection’ section of the online SAS submission form. Note: If the condition is listed, supporting evidence is not usually required.

TGA / STATE HEALTH AUTHORITY

PATIENT DOCTORAPPROVING

AUTHORITIES

DISCUSSION WITH DOCTOR1 DOCTOR APPLIES FOR

REQUIRED APPROVALS2

DOCTOR PRESCRIBES MEDICINAL CANNABIS4 APPROVAL GRANTED BY TGA /

STATE AUTHORITY (IF RELEVANT)3

1 2


ACCESSING MEDICINAL CANNABIS IN AUSTRALIA

WHAT ARE THE WAYS YOU CAN ACCESS MEDICINAL CANNABIS?

SAS Category B – application pathway (most common)

Special Access Scheme (SAS) B is an application pathway accessible to medical practitioners wanting to prescribe a medication for a patient where the unapproved good is not deemed to have an established usage history. An approval letter from the TGA and relevant State health department is required for a schedule 8 medicinal cannabis product before the therapeutic good may be prescribed by a doctor. Schedule 4 products (CBD only) require just TGA approval.

A medical practitioner can apply to prescribe a medicinal cannabis product for a single patient through the Special Access Scheme (SAS) Category B and the relevant State health department, using one single application via sas.tga.gov.au.

The TGA has committed to assessing applications within 48 hours so approvals have become very streamlined.

AUTHORISED PRESCRIBER

To prescribe medicinal cannabis for a group of patients with the same condition a medical practitioner can apply to become an Authorised Prescriber.

When a medical practitioner becomes an Authorised Prescriber, this means they do not need to notify the TGA each time they prescribe the cannabis product, but instead must report to the TGA the number of patients treated for each product every 6 months.

The medical practitioner must also seek endorsement for their application from a Human Research and Ethics Committee (HREC) who will assess not only the safety of the cannabis product for the condition, but also the suitability of the medical practitioner.

PLEASE NOTE: Before the medical practitioner applies to become an Authorised Prescriber it is recommended they process a minimum of five SAS B applications first to illustrate their understanding of prescribing medicinal cannabis. The HREC committee will also want to understand how a clinician has gained insight/expertise with medicinal cannabis. There are a number of courses both online and delivered face to face which would be considered an appropriate level of education.

01

02

03 SAS CATEGORY A – FOR TERMINALLY ILL PATIENTS

In the case of medicinal cannabis, SAS A is only relevant for clinicians wanting to import a specific medicinal cannabis product that is not currently available in Australia.

Category A is a notification pathway which can be accessed by a prescribing medical practitioner for patients who are seriously ill with a condition from which death is reasonably likely to occur within months, or from which premature death is reasonably likely to occur in the absence of early treatment. Supply of unapproved medicines to patients under Category A does not require TGA approval therefore it ensures timely access to effective therapy under the supervision of a dedicated medical practitioner. This is the only mechanism under the Therapeutic Goods Act and Regulations whereby terminally ill patients should be able to access medicines “immediately” without the requirement of approvals. However, as this pathway is only available for medicinal cannabis products not already in Australia, it is rarely used.

Please note: The SAS A scheme is not frequently used as the SAS B scheme is now more streamlined and the approvals process more efficient.

Support for medical practitionersLittle Green Pharma can support practitioners with the application process for State and Federal approvals to access medicinal cannabis. Alternatively, practitioners can visit: https://sas.tga.gov.au/ to register to apply for medicinal cannabis.

If you would like to learn more about the scientific evidence to support medicinal cannabis as an alternative treatment, or need assistance in processing a SAS B application or becoming an Authorised Prescriber, the Little Green Pharma team are here to help.

Our national team can be contacted for further information or assistance for authorised prescribers on 1300 118 840.


HOW DOES MEDICINAL CANNABIS WORK?

How does Medicinal Cannabis Work?

The Endocannabinoid System34,35

THE HUMAN ENDOCANNABINOID SYSTEM 34,35

CBD and THC fit like a lock and key into existing human cell receptors. These receptors are part of the endocannabinoid system which impact physiological processes affecting pain modulation, memory and appetite and also has anti-inflammatory effects and other immune system responses. The endocannabinoid system compromises two types of receptors, CB1 and CB2, which serve distinct functions in human health and well-being.

The identification of cannabinoid receptors

triggered an exponential growth of studies exploring

the endocannabinoid system and its regulatory

functions in health and disease. This system

has been implicated in a growing number of

physiological functions, both in the central and

peripheral nervous systems and in peripheral organs.

TETRAHYDROCANNABINOL

THC

CANNABIDIOL

CBD

CBD has low affinity for CB1 or CB2 receptors but has powerful indirect

effects still being studied.

CB1

CB2

CB1 receptors are primarily found in the brain and central

nervous system and to a lesser extent in other tissues.

CB2 receptors are mostly in the peripheral organs

especially cells associated with immune system.

RECEPTORS ARE FOUND ON CALL SURFACES

NEUROTRANSMITTERS

RECEPTORS

PRESYNAPTIC (SENDING NEURON)

CANNABINOID RECEPTOR

The endocannabinoid system (ECS) is a neurotransmitter system within the body made up of endogenous G-protein-coupled cannabinoid receptors (CB1 and CB2) and plays an important part in the regulation of homeostasis within the body. The ECS is found in all vertebrates (and even some invertebrates) and is thought to have an impact on many physiological symptoms such as sleep, stress, pain, appetite, memory, digestion and anxiety.

The body produces its own cannabinoids, called endocannabinoids. It is also triggered by cannabinoids from the cannabis plant of which THC and CBD are the most well-known and most extensively researched. CB1 receptors are located in abundance in the central and peripheral nervous system as well as the gastrointestinal and urinary tracts. CB1 receptors are believed to impact pain, sleep, appetite and even memory. CB2 receptors are found mostly in the immune system (tonsils, spleen, lymph nodes) and are responsible for the anti-inflammatory nature of cannabis. There is a very low concentration of CB1 and CB2 receptors in the brainstem, therefore cardiorespiratory depression and death resulting from cannabinoid consumption is almost impossible, in contrast to opioids.


The best studied and most abundant cannabinoids are Δ 9-tetrahydrocannabinol (THC) and cannabidiol (CBD).

The cannabis plant contains up to 545 chemical compounds including 114 different cannabinoids which may interact with the body’s cannabinoid receptors.36

Cannabinoids explained

CANNABINOIDS EXPLAINED

WHY IS THC:CBD RATIO IMPORTANT FOR PRODUCT SELECTION?

The THC:CBD ratio helps prescribers to identify products that may treat their patient’s condition, most effectively.

THC is a cannabinoid that has been shown to help patients treat chronic pain, inflammation, spasticity, and nausea. It also has intoxicating effects.

CBD is a non-intoxicating cannabinoid typically prescribed for seizures, pain, anxiety and inflammation. CBD is non-addictive and less potent than THC with very low toxicity.

THC and CBD may work synergistically, while CBD also antagonises the adverse side effects associated with THC.

Cannabis formulations have different ratios of THC to CBD. Each formulation:

• Provides different therapeutic effects.

• Interacts differently with each person’s endocannabinoid system and biochemistry.

• Can have a different side effect profile in patients.

Potential effects of THC & CBD 29,37

CBD (Cannabidiol)

THC (Tetrahydrocannabinol)

Analgesic Analgesic

Anti-inflammatory Anti-inflammatory

Anti-convulsive Anti-convulsive

Antiemetic Antiemetic

Sleep Assistance Sleep Assistance

Neuroprotective Neuroprotective

Appetite Stimulation Appetite Stimulation

Reduces the intoxicating effect of THC Intoxication

Anti-anxiety/Anti-depressant

Improved cognition

Potential effects of principal constituents: THC & CBD

TYPICAL RATIOS 31 (ALSO KNOWN AS STRENGTH OR POTENCY)

1:20

CBD 50

1:100

lITTlE Psychoactive

effect

NO Psychoactive

effect

lITTlE OR NO Psychoactive

effect

CBD DOMINANT<1mg/mL THC, 20mg/mL CBD

<0.2mg/mL THC, 20mg/mL CBD

<1.5mg/mL THC, 100mg/mL CBD

1:1lESS

Psychoactive effect

BALANCED THC:CBD10mg/mL THC, 10mg/mL CBD

4:1Psychoactive

effect lIKElY

THC DOMINANT20mg/mL THC, 5mg/mL CBD

01

02

RESEARCH THC & CBD

*Please note the evidence provided generally relates to cannabis treatment using the named active ingredients and is not be taken as specific evidence for the efficacy of any listed products.

EVIDENCE SUPPORTS THE USE OF HIGH CBD MEDICINAL CANNABIS FORMULATIONS IN THE TREATMENT OF*:

Irritable Bowel Syndrome 7,9

Insomnia 11,12

Anorexia 13,16

Chronic Pain 3,24

Refractory Epilepsy 25-28

Anxiety 22-23

Austism 29

EVIDENCE SUPPORTS THE USE OF BALANCED THC/CBD MEDICINAL CANNABIS FORMULATIONS IN THE TREATMENT OF*:

Spasticity, MS 19-21

Irritable Bowel Syndrome 7,9

Insomnia 11,23

PTSD 16,17

Chronic Pain 3,22,23

EVIDENCE SUPPORTS THE USE OF HIGH THC MEDICINAL CANNABIS FORMULATIONS IN THE TREATMENT OF*:

Chronic Pain 1-3

Chemo induced nausea & vomiting 4-6

Irritable Bowel Syndrome 7-9

Insomnia 10-13

Cachexia 13-16

PTSD 16,17

Spasticity, MS 17-18

DOSAGE AND FORMULATIONS SHOULD BE SELECTED BASED ON INDIVIDUAL

PATIENT CIRCUMSTANCES.

THC dominant

CBD

CBD THC

THC

CBD dominant


CANNABINOIDS EXPLAINED

ADDITIONAL CANNABINOIDS

Research into the many lesser known cannabinoids in cannabis is continuing globally at centres such as The Lambert Initiative in Sydney and Dedi Meiri’s Laboratory of Cancer Biology and Cannabinoid Research, in Israel. Below is an outline of what we currently know:

Cannabinoid Potential effects 36,37

THC (Tetrahydrocannabinol)Analgesic, anti-Inflammatory, reduced spasm, antiemetic, sleep, intoxication, neuroprotective, appetite stimulation

CBD (Cannabidiol) Analgesic, anti-Inflammatory, anti-convulsive, antiemetic, sleep, reduces the intoxicating effect of THC, anti-anxiety, anti-depressant, neuroprotective, appetite stimulation, improved cognition

THCA* (Tetrahydrocannabinolic acid) Anti-inflammatory, antiemetic, reduced spasm - non-intoxicating

Anti-inflammatory, antiemetic, reduced spasm- non-intoxicating (seizure), appetite stimulation, sleep, neuroprotective

CBDA (Cannabidiolic acid)Anti-inflammatory, antiemetic, reduces spasm

CBG (Cannabigerol) Analgesic, anti-spasticity, anti-anxiety

CBC (Cannabichromene)Anti-inflammatory, analgesic, anti-anxiety, anti-depressant

CBN (Cannabinol)Anti-convulsive, analgesic, sleep, anti-inflammatory

THCV (Tetrahydrocannabivarin) Appetite suppressant, aids memory, anti-anxiety

THE ENTOURAGE EFFECT 37,55

The ‘entourage effect’, proposes whole plant cannabis extract made up of hundreds of active ingredients, including terpenes, flavonoids and cannabinoids, is more effective than isolated cannabinoids or terpenes used individually to treat a condition.37

Investigations have shown whole plant extracts (with single cannabinoid dominance) are up to four times more effective than isolated single cannabinoids.56,57

Research is on-going into the synergistic potential of whole plant extract in a variety of conditions, but generally whole plant extract is preferred.

03 04

CBDa

THCv

CBC

CBG

CBNTHC

CBD THCa


POTENTIAL OPIOID-SPARING EFFECTS OF MEDICINAL CANNABIS

Potential opioid-sparing effects of medicinal cannabis

There is a growing body of evidence supporting the use of medicinal cannabis as an adjunct therapy to reduce dependence on opioids, resulting in improved patient pain control and side effect profile.

• Haroutounian (2016) showed a 44% reduction in opioid use in pain patients using medicinal cannabis. Improved pain and pain interference scores were recorded at six months in a prospective study investigating long-term use of medicinal cannabis in 274 patients.58

• Boehnke (2006) followed 244 patients using medicinal cannabis for chronic pain and found a 64% decrease in opioid use, 45% improvement in quality of life, as well as reduced side effects.59

HOW CAN MEDICINAL CANNABIS AND OPIOIDS WORK TOGETHER? 63

Cannabinoids exhibit analgesic effects and potentiate opioids’ anti-nociceptive effects. Preclinical and clinical studies demonstrate that THC may enhance opioids’ analgesic effects in a synergistic manner. The rationale behind cannabinoid-opioid synergism includes:

• CB2 receptors indirectly stimulate opioid receptors located in primary afferent pathways

• CB1 and CB2 agonists can induce antinociception by increasing opioid precursor’s gene expression or via release of endogenous opioids.

• Cannabinoid antagonists are shown to reverse antinociception induced by morphine

STUDIES

Cannabis has also been shown to prevent tolerance and withdrawal from opioids and is increasingly being used to combat opioid addiction. Interestingly, in July 2018 the US state of New York made ‘opioid replacement’ a qualifying condition for medicinal cannabis.60

In two recent studies, the first published in the Journal of the American Medical Association (2018), a reduction in opioid scripts was observed in US states which had introduced medicinal cannabis legalisation.61 This observation is in-line with the Bachhuber (2014) review which saw a 25% reduction in opioid related deaths in states where medicinal cannabis was legalised.62 Whilst this evidence is not yet conclusive the body of evidence is mounting for the use of medicinal cannabis to reduce opioid use, side effects and addiction.

DROP IN OPIOID HOSPITALISATION RATES FOR STATES WHERE MEDICINAL CANNABIS IS LEGAL62

USA24.8%

02

01


1/20000

1/1000

1/1000

1/199

1/150

1/100

1/50

1/50

1/50

1/38

1/30

1/24

1/21

1/20

1/20

1/16

1/15

1/10

1/10

1/10

1/8

1/8

1/6

POTENTIAL OPIOID-SPARING EFFECTS OF MEDICINAL CANNABIS

RISK OF TOXICITY 4,64

The risk of severe, adverse events or dependence is low with medicinal cannabis. However, concurrent use of other drugs may mask the effects of cannabis and severe toxicity. THC MEDIAN LETHAL DOSE: >800MG /KG

ACTIVE / LETHAL DOSE RATIO AND DEPENDENCE POTENTIAL OF PSYCHOACTIVE DRUGS65

03 04

Is medicinal cannabis safe?

THC MEDIAN LETHAL DOSE: >800MG /KG

CBD IS SAFE FOR HUMANS: 1000MG/ KG

CANNABISNITROUS OXIDE K

VERY HIGH -

HIGH -

MODERATE/HIGH -

MODERATE -

MODERATE/LOW -

LOW -

VERY LOW -LSD

S MESCALINES PSILOCYBIN

PENTOBARBITAL ◉

ALCOHOL ◉ROHYPNOL ◉

NICOTINE ▲

▲ COCAINE

▲ MDMA▲ CAFFEINE

HEROIN

MORPHINE

K KETAMINE

EPHEDRA ▲

DEPE

NDE

NCE

PO

TEN

TIAL

ACTIVE DOSE / LETHAL DOSE

0.001 0.002 0.01 0.02 0.1 0.2

NARCOTICS ◉ DEPRESSANTS ▲ STIMULANTS K ANAESTHETICS S HALLUCINOGENS CANNABIS

Ranking substances by their ratios of lethal dose to effective dose gives an indication of how likely each is to precipitate an acute fatal reaction.

Medicinal cannabis is considerably safer than alcohol64. To put this into perspective, a patient would need to consume 147 doses of 7% THC using a vaporizer within a 15 minute period to get close to reaching the lethal dose.

CANNABIS

PSILOCYBIN

LSD

ASPIRIN*

NITROUS OXIDE

PROZAC

PHENOBARBITAL

DMT

CAFFEINE*

KETAMINE

ROHYPNOL

MESCALINE

TOBACCO*

METHADONE

CODEINE

MDMA

COCAINE

METHAMPHETAMINE

DEXTROMETHORPHAN

ALCOHOL

ISOBUTYL NITRATE

GHB

HEROIN

SCHEDULE I (Illegal, Dangerous)

SCHEDULE II or III (Prescribable, Dangerous)

SCHEDULE IV or V (Prescribable, Low Danger)

UNSCHEDULE (Legal Over the Counter)

VERY NON-TOXIC GETTING MORE TOXIC APPROACHING POISON

Therapeutic Ratio is the ratio of Effective Dose – Amount that works over Lethal Dose – Amount that kills. For example., Alcohol’s 1/10 Therapeutic Ratio means that 2 shots get you drunk, 20 shots can kill you.

Marijuana’s Therapeutic Ratio can not resonably be measured – it is so non-toxic it can’t cause overdose.

*Source: Erowid.org

DEA DRUG SCHEDULES

• Cannabis has a low addiction rate as compared to alcohol, caffeine and other known addictive drugs like opioids.

• The LD value is estimated to be between 1:20,000 and 1:40,000 for cannabis. It is estimated 628kg of cannabis would need to be smoked in 15 minutes to have a lethal effect.66


There are important considerations for each method67 (adapted from MacCallum, Russo, 2018):

There are a multiple delivery routes for medicinal cannabis.In Australia, the oral route (oil based formulation) is most common followed by buccal spray and vaporisation.

METHODS OF ADMINISTRATION

Methods of Administration

Onset and duration of inhaled vs oral medicinal cannabis68

OVERVIEW OIL BUCCAL SPRAY VAPORISATION

ONSET (minutes) 60-180 15-45 5-10

DURATION (hours) 6-8 6-8 2-4

ABSORPTION

From the GI tract and metabolized in the liver before entering the

bloodstream

Through the lungs directly into bloodstream

PRO

Discrete, convenient, odorless, beneficial for chronic conditions/

symptoms where control over longer periods of time is sought

Faster onset of action than oil

Beneficial for acute or episodic symptoms

CON Titration difficulty due to

delayed onset of actionInconsistent dispensing

No vaporisation devices are currently approved by TGA. Devices may be

expensive, may not be portable and require patient mobility.

100

80

60

40

20

00 1 2 3 4 5 6 7 8+

THC

Conc

enta

rtio

n (m

g/m

L)

VAPORISED CANNABIS

Time (Hours)

INGESTED CANNABIS

Reference: Grotenhermen F. “Some practice-relevant aspects of the pharmacokinetics of THC”.

Forsch Komplementarmed. 1999 Oct;6 Suppl 3:37-9.

CANNABIS OILS

Little Green Pharma has developed oil-based products. This is the preferred and most common method of administration in Australia. As advised by the TGA, “Given the slower onset and longer duration, it is expected that taking medicinal cannabis products orally would be more useful for medical conditions or symptoms where control over longer periods of time is sought— similar to the use of slow release medications”.4

Cannabis oil is made by extracting concentrated resin from the cannabis flower, and diluting the resin with a pharmaceutical grade oil to make a finished oil product of a defined concentration measured in mg of THC and mg of CBD per mL of oil.


There is currently no set dosing regime, however, titrating guidelines are available.

When considering what dose to prescribe for patients, practitioners need to consider and tailor this depending on:

• Any previous experience with cannabis • If a patient can advise their tolerance (based on previous experience)

• Symptoms

• Expectations

• Choice of products relating to THC & CBD ratio

Patients require a titration period for ingested cannabis oil to determine their optimal dose.

DOSING

Dosing

Dosing Guidelines (start low, go slow)

The ‘start low, go slow’ approach to medicinal cannabis

is universal, as each patient will require a different dose

to achieve a therapeutic effect. MacCallum and Russo’s

2018 guidelines suggest increasing the dose every

second day until therapeutic benefit is achieved without

significant side effects. If side effects outweigh clinical

benefit, then the patient should return to a dose which

was tolerable. The TGA and/or State health department

will set a maximum allowable dose for each patient based

on the treatment plan provided by the doctor. A good rule

of thumb is maximum 30mg THC/ day. If the maximum

dose is reached and no side effects or therapeutic benefit

is achieved, an application may need to be made to

increase the daily maximum dose of THC.

Dosing Guidelines (start low, go slow)67

Dosing remains highly individualised and relies on each person finding the dose that works best for them where the benefits are maximised and any unwanted adverse effects are minimised. The rate and speed of dose adjustment will depend on individual response.

The TGA recommends a ‘start low, go slow’ approach to dosing, in line with international guidelines.29-31

The titration calendar is an example only and has been adapted from MacCallum and Russo (2018), ‘Practical considerations in medical cannabis administration and dosing’.

Example OnlyINSTRUCTIONS FOR USE HOW TO START CANNABIS OIL66

START IN THE EVENING1

START LOW 2.5mg THC 1.25mg THC if elderly, frail or paediatric

2

TITRATE SLOWLY Until therapeutic effect achieved

3

1:1 ratio medicationLGP Classic 10:10

(10mg/mL THC : 10mg/mL CBD)

DAY 1-3 DAY 4-6 DAY 7-9 DAY 10-12 DAY 13-15 DAY 16-18

Morning Nil 0.25 mL 0.25 mL 0.50 mL 0.50 mL 0.75 mL

Evening 0.25 mL 0.25 mL 0.50 mL 0.50 mL 0.75 mL 0.75 mL


DOSING

WARNING/ PRECAUTIONS

General precautions for the prescription of medicinal cannabis is advised in the following patient groups:• severe cardio-pulmonary disease because of occasional hypotension,

hypertension;• syncope, or tachycardia;• history of substance abuse, including alcohol abuse, because such individuals

may be more prone to abuse cannabis and medical cannabis preparations;• ongoing chronic hepatitis C should be strongly advised to abstain from daily

cannabis use, as this has been shown to be a predictor of steatosis severity in these individuals;

• concomitant therapy with sedative-hypnotics or other psychoactive drugs because of the potential for additive or synergistic CNS depressant or psychoactive effects;

• use in hepatic and renal impairment. Medicinal cannabis should be used with caution be used in patients with severe liver or renal disease.

CONTRAINDICATIONS WITH CANNABIS4

The Australian Therapeutic Goods Administration (TGA) has advised that medicinal cannabis, should not be used in patients who: • have a history of hypersensitivity to any cannabinoid; • have a history of psychotic disorders (especially schizophrenia); or • are confirmed pregnant, likely to be pregnant or planning on becoming pregnant.

The most clinically significant interactions may occur when cannabis is taken with other CNS depressant drugs such as sedative-hypnotics or alcohol.

Patients taking fentanyl (or related opioids) and anti-psychotic medications (clozapine or olanzapine) may also be at risk of experiencing adverse effects if co-consuming medicinal cannabis or cannabinoids.

DRIVING / OPERATING MACHINERY4

Patients are advised not to drive or use machinery when taking cannabis containing the cannabinoid THC. Cannabis can stay in the system for several days after the last dose and patients run the risk of positive drug tests in the workplace or roadside police testing.

DRUG INTERACTIONS29,69

• Drugs metabolised by CYP450• Warfarin and other blood thinners (THC and CBD can increase the levels of these drugs in the system)

• Use with alcohol, barbiturates and benzodiazepines (increased central nervous system depressive effects)

• Clobazam (CBD can increase levels)

• Theophylline (THC and CBD can decrease levels)

SIDE EFFECTS MEDICINAL CANNABIS67

01

02

03

05

04Important Considerations

DRUGS IMPACTING THC AVAILABILITY

DRUGS THAT POTENTIATE THC AVAILABILITY AND INCREASES BIOAVAILABILITY & SIDE EFFECTS

DRUGS THAT INHIBIT THC AVAILABILITY AND DECREASE ITS EFFECTIVENESS

Antidepressants (e.g., fluoxetine, fluvoxamine)

Proton pump inhibitors (e.g., omeprazole)

Macrolides (e.g., clarithromycin, erythromycin)

Antimycotics (e.g., itraconazole, fluconazole, ketoconazole, miconazole)

Calcium antagonists (e.g., diltiazem, verapamil)

HIV protease inhibitors (e.g., ritonavir)

Amiodarone

Isoniazid

Rifampicin

Carbamazepine

Phenobarbital

Phenytoin

Primidone

Rifabutin

Troglitazone

St John’s wort


Side Effect Most Common Common Rare

Drowsiness/ fatigue

Dizziness

Dry mouth

Cough, phlegm, bronchitis (smoking only)

Anxiety

Nausea

Cognitive effects

Euphoria

Blurred vision

Headache

Orthostatic hypotension

Toxic psychosis/ paranoia

Depression

Ataxia/ dyscoordination

Tachycardia (after titration)

Cannabis hyperemesis

Diarrhoea

PATIENT SUITABILITY & TREATMENT PLAN

DETERMINE SUITABILITY FOR TREATMENT

01 Consider cannabis when other medicines are not controlling symptoms or cause unwanted side effects in patients.

02 Assess patients on a case by case basis – what are the objectives?

03 Can the patient afford medicinal cannabis?

04 Document previous treatment history and medicines used.

05 Conduct risk to benefit analysis – will this treatment suit this patient? e.g. driving/working.

06 Is there supporting evidence for the patient’s condition?

07 Consider appropriate ratios of THC and CBD based on medical condition(s) and patient e.g. age, previous exposure to cannabis, weight/metabolism.

08 Choose product based on the above.

PHARMACOLOGY OF MEDICINAL CANNABIS

PATIENT MANAGEMENT & MONITORING INITIAL CONSULATION & ASSESSMENT

Some considerations to discuss with patients include:Travel — care should be taken when travelling with prescribed medicines, particularly medical cannabis containing THC.

Contacting local embassies or travel companies (e.g. cruise) is recommended.

PATIENT’S CONSULTATION

Clinical examination

Pain assessment score

Symptoms assessment scale

Quality of life

Suitability for cannabis

Consider consulting patient’s case with colleagues if appropriate

WHAT TO MONITOR

MONITOR USING PHYSIOLOGIC PARAMETERS

MEASURE PROGRESS

WHAT TO MONITOR

A monitoring plan should look for the following:

01 Efficacy: how well are the patient’s symptoms being managed e.g. improvement in pain scores, sleep.

02 Side effects: may need to adjust the dose accordingly.

03 Therapeutic response. For patients with symptom improvement, consideration may be given to reduction of other medications (e.g. opioids for patients with pain improvement, sleeping aids for patients with improved sleep.

04 No therapeutic response. If a patient does not have a therapeutic response, after reaching the maximum therapeutic dose, no therapeutic response after achieving the maximum recommended dose, consider a different ratio of THC and CBD.


references1. Mikuriya TH., ‘Marijuana in medicine: past, present and future’, California Medicine, vol. 110 (1), 1969, pp. 34-40.

2. Fankhauser M., ‘History of cannabis in Western Medicine’ in: Grotenhermen F, Russo E, eds. Cannabis and Cannabinoids, New York, 2002, The Haworth Integrative Healing Press, 2002, pp. 37–51.

3. Zuardi AW, ‘History of cannabis as a medicine: a review’, Braz J Psychiatry, Vol. 28 (2), 2006, pp. 153-7.

4. Therapeutics Goods Administration, ‘Guidance for the use of medicinal cannabis in Australia, Overview’, Australian Government, Department of Health, Therapeutic Goods Administration, 2017, https://www.tga.gov.au/sites/default/files/guidance-use-medicinal-cannabis-australia-overview.pdf (accessed 8 April 2019).

5. Rafael de Mello Schier, A, et al., ‘Cannabidiol, a Cannabis sativa constituent, as an anxiolytic drug’, Revista Brasileira de Psiquiatria, vol. 34(Supl1), 2012, pp. S104-S117

6. Crippa, JAS, et al., ‘Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report’, Journal of Psychopharmacology, vol. 25(1), 2010, pp. 121-130.

7. Blake, DR, et al., ‘Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis’, Rheumatology. Vol. 45, 2006, pp. 50-52.

8. Hammell, DC, et al., ‘Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis’, European Journal of Pain, vol. 20 (6), 2016, pp. 936-948.

9. Bar-Lev Schleider, L, et al., ‘Prospective analysis of safety and efficacy of medical cannabis in large unselected population of patients with cancer’, European Journal of Internal Medicine, vol. 49, 2018, pp. 37-43..

10. Beal, JE, et al., ‘Dronabinol as a Treatment for Anorexia Associated with Weight Loss in Patients with AIDS’, Journal of Pain and Symptom Management, vol. 10 (2), 1995, pp. 89-97.

11. Nelson, K et al., ‘A phase II study of delta-9-tetrahydrocannabinol for appetite stimulation in cancer-associated anorexia’, Journal of Palliative Care, vol. 10 (1), 1994, pp. 14-18.

12. Waissengrin, B, et al., ‘Patterns of Use of Medical Cannabis Among Israeli Cancer Patients: A Single Institution Experience’, Journal of Pain and Symptom Management, vol. 49 (2), 2015, pp. 223-230.

13. Peng, M, et al., ‘Medical marijuana as a therapeutic option for cancer anorexia and cachexia: A scoping review of current evidence’, Journal of Pain Management, vol. 9 (4), 2016, pp. 435-447.

14. Cyr, et al., ‘Cannabis in palliative care: current challenges and practical recommendations’, Annals of Palliative Medicine, vol. 7 (4), 2018, pp. 463-477.

15. Muller-Vahl, KR, et al., ‘Treatment of Tourette Syndrome with Delta-9- Tetrahydrocannabinol (D9 -THC): No Influence on Neuropsychological Performance’, Neuropsychopharmacology, vol. 28, 2003, pp. 384-388.

16. Muller-Vahl, KR and Schneider, U., ‘Combined Treatment of Tourette Syndrome with Δ9-THC and Dopamine Receptor Antagonists’, Journal of Cannabis Therapeutics, vol. 2(3-4), 2002, pp. 145-154.

17. Tomida, I, Pertwee, RG and Azuara-Blanco, A, ‘Cannabinoids and glaucoma’, British Journal of Opthamology, vol. 88 (5), 2004, pp. 708-713.

18. Di Carlo, G and Izzo, A ‘Cannabinoids for gastrointestinal diseases: potential therapeutic applications’, Drugs, vol. 12 (1), 2003, pp. 39-49.

19. Naftali, T., et al., ‘Cannabis Induces a Clinical Response in Patients With Crohn’s Disease: A Prospective Placebo-Controlled Study’, Clinical Gastroenterology and Hepatology, vol. 11, 2013, pp. 1276–1280.

20. Szabady, RL., et al., Intestinal P-glycoprotein exports endocannabinoids to prevent inflammation and maintain homeostasis. The Journal of Clinical Investigation. 2018; 1-13.

21. Lotan, I, et al., ‘Cannabis (Medical Marijuana) Treatment for Motor and Non–Motor Symptoms of Parkinson Disease: An Open-Label Observational Study’, Clinical Neuropharmacology, vol. 37 (2), 2014, pp. 41-44.

22. Venderova, K, et al., ‘Survey on Cannabis Use in Parkinson’s Disease: Subjective Improvement of Motor Symptoms’, Movement Disorders, vol. 19 (9), 2014, pp. 1102-1106.

23. Shohet, A, et al., ‘Effect of medical cannabis on thermal quantitative measurements of pain in patients with Parkinson’s disease’, European Journal of Pain, vol. 21, 2017, pp. 486-493.

24. Betthauser, K, Pilz, J and Vollmer, LE, ‘Use and effects of cannabinoids in military veterans with posttraumatic stress disorder’, American Journal of Health-System Pharmacy, vol. 72, 2015, pp. 1279-1284.

25. Passie et al., ‘Mitigation of post-traumatic stress symptoms by Cannabis resin: A review of the clinical and neurobiological evidence’, Drug Test Analysis, vol. 4(7-8), 2012, pp. 649-659.

26. Ferguson G and Ware MA., ‘Review Article: Sleep, Pain and Cannabis’, Journal of Sleep Disorders & Therapy, 4 (2), vol. 2015, pp. 1-5.

27. Russo, EB, Guy, GW and Robson, PJ., ‘Cannabis, Pain and Sleep: Lessons from Therapeutic Clinical Trials of Sativex, a Cannabis-Based Medicine’, Chemistry & Biodiversity, vol. 4, 2007, pp. 1729-1744.

28. Australian Government Department of Health, Submission to the Senate Community Affairs References Committee, Senate inquiry into the current barriers to patient access to medicinal cannabis in Australia, January 2020.

29. Abramovici, H., ‘Information for Health Care Professionals: Cannabis (marihuana, marijuana) and the cannabinoids’, Health Canada, 2013, https://www. canada.ca/en/health-canada/services/drugs-medication/cannabis/information-medical-practitioners/information-health-care-professionals-cannabis-cannabinoids.html (accessed 17 January 2019).

30. Landschaft, Y., ‘The Green Book: The Official Guide to Clinical Care in Medical Cannabis’, Israeli Ministry of Health, 2017, https://www.xn--4dbcyzi5a. com/en/2018/01/medical-cannabis-official-israeli-clinical-guide/ (accessed 28 January 2019).

31. Nederlandse Associatie voor legale Cannabis en haar Stoffen als Medicatie, ‘The Dutch Medicinal Cannabis Program: Indications for medicinal cannabis use’, The Office of Medical Cannabis, 2008, http://www.ncsm.nl/english/information-for-patients/when-to-use-it-indications (accessed 12 November 2018).

32. Bonn-Miller, MO, ‘Labeling Accuracy of Cannabidiol Extracts Sold Online’, Journal of the American Medical Association, vol. 318 (17), 2017, pp. 1708-1709.

33. Vandrey, R, ‘Cannabinoid Dose and Label Accuracy in Edible Medical Cannabis Products’, Journal of the American Medical Association, vol. 313 (24), 2015, pp. 2491-2492.

34. ElSohly M., ‘Chemical Constituents of Cannabis. Cannabis and Cannabinoids – Pharmacology’, Toxicology and Therapeutic Potential, 2002, pp: 27-36.

REFERENCES 35. Aggarwal, SK., ‘Cannabinergic pain medicine: a concise clinical primer and survey of randomized controlled trial results’, Clinical Journal of Pain, vol. 29 (2) 2013, pp. 161-171.

36. Ahmed SA., et al. ‘Minor oxygenated cannabinoids from high potency Cannabis sativa L’, Phytochemistry , vol. 117, 2015, pp. 194-199.

37. Russo, EB, ‘Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects’, British Journal of Pharmacology, vol. 163, 2011, pp. 1344-1364.

38. Whiting PF, Wolff RF, Deshpande, S, et al., ‘Cannabinoids for Medical Use A Systematic Review and Meta-analysis’, JAMA, vol. 3113 (24), 2015, pp. 2456-2473.

39. Lynch, E and Campbell, F., ‘Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials’, British Journal of Clinical Pharmacology, vol. 72 (5), 2011, pp. 735–744.

40. Ware, M, Wang T, Shapiro, S, et al., ‘Smoked cannabis for chronic neuropathic pain: a randomized controlled trial’, CMAJ, vol. 182 (14), 2010, pp. 694-701.

41. Machado Rocha, FC et al., ‘Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis’, European Journal of Cancer Care, vol. 17, 2008, pp. 431-443.

42. Rock, EM et al., ‘Tetrahydrocannabinolic acid reduces nausea-induced conditioned gaping in rats and vomiting in Suncus murinus’, British Journal of Pharmacology, vol. 170, 2013, pp. 641-648.

43. Cameron, C., et al., ‘Use of a Synthetic Cannabinoid in a Correctional Population for Posttraumatic Stress Disorder, Related Insomnia and Nightmares, Chronic Pain, Harm Reduction, and Other Indications A Retrospective Evaluation’, Journal of Clinical Phsychopharmacology, vol. 35 (5), 2014, pp. 559-564.

44. Petro DJ, Ellenberger C., ‘Treatment of human spasticity with delta9-tetrahydrocannabinol’, Journal of Clinical Pharmacology, vol. 21, 1981, pp. 413S-6S.

45. Ungerleider JT, et al., ‘Delta-9-THC in the treatment of spasticity associated with multiple sclerosis’ Adv Alcohol Substance Abuse, vol. 7, 1987, pp. 39-50.

46. Notcutt, WG., ‘Clinical Use of Cannabinoids for Symptom Control in Multiple Sclerosis’, Neurotherapeutics, vol. 12, 2015, pp. 769-777.

47. Wade, DT., et al., ‘Meta-analysis of the efficacy and safety of Sativex (nabiximols), on spasticity in people with multiple sclerosis’ Multiple Sclerosis, vol. 16 (6), 2010, pp. 707-714.

48. Zajicek JP, Hobart JC, Slade A, et al,. ‘Multiple Sclerosis and Extract of Cannabis: results of the MUSEC trial’, J Neurology, Neurosurgery and Psychiatry, vol. 83, 2012, pp. 1125-1132.

49. Portenoy, RK, et al., ‘Nabiximols for Opioid-Treated Cancer Patients With Poorly-Controlled Chronic Pain: A Randomized, Placebo-Controlled, Graded-Dose Trial’, The Journal of Pain, vol. 13 (5), 2012, pp. 438-449.

50. Costa, B., et al., ‘The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain’, European Journal of Pharmacology, vol. 556, 2007, pp. 75-83.

51. Devinsky, O., et al., ‘Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial’, The Lancet, vol. 15 (3), 2015, pp. 270-278.

52. Devinsky, O., et al., ‘Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome’, The New England Journal of Medicine, vol. 376 (21), 2017, pp. 2011-2020.

53. Thiele, EA, et al., ‘Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial’, The Lancet, vol. 391, 2018, pp. 1085-1096.

54. Tzadok, M., et al., ‘CBD-enriched medical cannabis for intractable paediatric epilepsy; The current Israeli experience’, Seizure vol. 35, 2016, pp. 41-44.

55. Russo, E and Guy, GW., ‘A tale of two cannabinoids: The therapeutic rationale for combining tetrahydrocannabinol and cannabidiol’, Medical Hypotheses, vol. 66, 2006, pp. 234-246.

56. Gallily, R., Yekhtin, Z. and Ondrej Hanus, L., ‘Overcoming the Bell-Shaped Dose-Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol’, Pharmacology & Pharmacy, vol. 6, 2015, pp. 75-85

57. Carlini EA., Karniol IG, ‘Renault PF, Schuster CR, Effects of marihuana in laboratory animals and in man’, British Journal of Pharmacology, vol. 50, 1974, pp. 299–309.

58. Haroutounian, S, et al., ‘The Effect of Medicinal Cannabis on Pain and Quality-of-Life Outcomes in Chronic Pain A Prospective Open-label Study’, Clinical Journal of Pain, vol. 32 (12), 2016, pp. 1036-1043.

59. Boehnke, KF et al., Medical Cannabis Use Is Associated With Decreased Opiate Medication Use in a Retrospective Cross-Sectional Survey of Patients With Chronic Pain. The Journal of Pain, 2016, vol, 17 (6): 739-744.

60. Lucas, P., ‘Cannabis as an Adjunct to or Substitute for Opiates in the Treatment of Chronic Pain’, Journal of Psychoactive Drugs, vol. 44 (21), 2012, pp. 125-133.

61. Bradford, AC., et al., ‘Association Between US State Medical Cannabis Laws and Opioid Prescribing in the Medicare Part D Population’, JAMA, vol. 178 (5), 2018, pp. 667-673.

62. Bachhuber et al., ‘Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, 1999-2010’, JAMA , vol. 174 (10), 2014, pp. 1668-1673.

63. Roberts, JD et al., ‘Synergistic affective analgesic interaction between delta-9-tetrahydrocannabinol and morphine’, European Journal of Pharmacology, Vol. 530, 2006, pp. 54-58.

64. Gable, RS, ‘Comparison of acute lethal toxicity of commonly abused psychoactive substances’, Addiction, Vol. 99, 2004, pp. 686-696.

65. Gable, RS, ‘Acute toxicity of drugs versus regulatory status’, J.M. Fish (ed.), Drugs and Society: US Public Policy, 2006. pp. 149-162.

66. Young, F, ‘In the Matter of Marijuana Rescheduling Petition’, US Department of Justice, DEA, 30 (2), 1998. pp. 137-147.

67. MacCallum C & Russo, E., ‘Practical considerations in medical cannabis administration and dosing’, European Journal of Internal Medicine, vol. 49, 2018, pp.12-19.

68. Grotenhermen, F., ‘Some practice-relevant aspects of the pharmacokinetics of THC’, Forsch Komplementarmed, Vol. 6 Suppl 3, 1999, pp. 37-39.

69. Watanabe, K., et al., ‘Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes’, Life Sciences, vol. 80 (15), 2007, 1415-1419.

70. National Institute for Health and Care Excellence; NICE guideline [NG144] Cannabis-based medicinal products (2019) https://www.nice.org.uk/guidance/ng144/chapter/Recommendations.

71. NZ ministry of health: https://www.health.govt.nz/ our-work/regulation-health-and-disability-system/medicinal-cannabis-agency/medicinal-cannabis-agency-information-health-professionals.

28 Healthcare Professional Guide for Medicinal Cannabis

Phone: 1300 118 840

Email: [email protected]

Website: littlegreenpharma.com

This is an unregistered medicine manufactured to pharmaceutical grade standards

Sponsor: Little Green Pharma, PO Box to: 690, West Perth WA 6872

Little Green Pharma Ltd. ABN 44 615 586 215.Date of preparation: June 2020.LGP_24062020 V2

Documents

Healthcare Professional Guide · As of Feb 2020, the TGA had approved medicinal cannabis for the treatment ... prescription of medicinal cannabis in one or more of the following country