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Publication of interim decisions amending, or not amending, the current Poisons Standard, June 2018

Scheduling medicines and poisons

7 June 2018

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1.2 Cannabidiol, cannabis and tetrahydrocannabinols

1. Advisory Committee on Medicines Scheduling (ACMS #23)

1.2 Cannabidiol, cannabis and tetrahydrocannabinols

Delegate's interim decision

The delegate's interim decision is to amend the Schedule 4 entry for cannabidiol, and the Schedule 8 and Appendix K entries for tetrahydrocannabinols and cannabis in the Poisons Standard to read as follows:

Schedule 4 Entry

CANNABIDIOL in preparations for therapeutic use where:

  1. cannabidiol comprises 98 per cent or more of the total cannabinoid content of the preparation; and
  2. any cannabinoids, other than cannabidiol, must be only those naturally found in cannabis and total 2 per cent or less of the cannabinoid content of the preparation.

Schedule 8

# TETRAHYDROCANNABINOLS when extracted from cannabis for human therapeutic use, when:

  1. included in products manufactured in accordance with the Narcotic Drugs Act 1967; and/or
  2. imported as therapeutic goods, or for use in therapeutic goods, for supply, in accordance with the Therapeutic Goods Act 1989; and/or
  3. in therapeutic goods supplied in accordance with the Therapeutic Goods Act 1989,
  4. except when:
    1. it is a product to which item 4, 8, 10, 11 or 12 of Schedule 5A to the Therapeutic Goods Regulations 1990 applies; or
    2. in hemp seed oil, containing 50 mg/kg or less of tetrahydrocannabinols when labelled with either of the following warning statements:
      1. Not for internal use; or
      2. Not to be taken; or
    3. separately specified in the NABIXIMOLS entry in this Schedule; or
    4. cannabidiol when included in Schedule 4.

Schedule 8

# CANNABIS (including seeds, extracts, resins and the plant, and any part of the plant) when prepared or packed for human therapeutic use, when:

  1. cultivated or produced, or in products manufactured[9] , in accordance with the Narcotic Drugs Act 1967; and/or
  2. for use in products manufactured in accordance with the Narcotic Drugs Act 1967; and/or
  3. imported as therapeutic goods, or for use in therapeutic goods, for supply, in accordance with the Therapeutic Goods Act 1989; and/or
  4. in therapeutic goods supplied in accordance with the Therapeutic Goods Act 1989,
  5. except:
    1. when it is a product to which item 4, 8, 10, 11 or 12 of Schedule 5A to the Therapeutic Goods Regulations 1990 applies; or
    2. cannabidiol when included in Schedule 4; or
    3. when separately specified in the NABIXIMOLS entry in this Schedule; or
    4. when in hemp seed oil for purposes other than internal human therapeutic use containing 50 mg/kg or less of cannabinoids.

Appendix K

CANNABIS except cannabidiol when included in Schedule 4.

TETRAHYDROCANNABINOLS except cannabidiol when included in Schedule 4.

Proposed implementation date: 1 October 2018

The delegate considers the Committee's proposed implementation date of 1 October 2018 as being reasonable and appropriate in the circumstances.

Reasons:

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate for the decision include:

  1. the risks and benefits of the use of a substance:
    • the overall risks and benefits remain the same as when last considered; and
    • the known risks with drug interactions and potential to affect liver function reinforce need to be a prescription medicine.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • as the substance should be used under medical guidance due to potential drug interactions and effect on liver function it should be clear that it is a prescription medicine and what constitutes a Schedule 4 vs Schedule 8 substance.
  3. the toxicity of a substance:
    • there is evidence of drug interactions and an effect on liver function.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • providing clarity to assist labelling and packaging.
  5. the potential for abuse of a substance:
    • little potential for abuse which reinforces Schedule 4 vs Schedule 8.
  6. any other matters that the Secretary considers necessary to protect public health:
    • This amendment is to clarify the entry following its implementation and does not seek to change the original scheduling decisions in a substantive manner.
    • Clarification of these entries is necessary to prevent their inadvertent or deliberate misinterpretation resulting in harm through Schedule 8 products being treated as Schedule 4 products, including not obtaining State authority to prescribe, and increased potential for diversion/misuse because of less restrictive storage and recording requirements.
Scheduling proposal

The pre-meeting scheduling proposal for cannabidiol, cannabis and tetrahydrocannabinols was published on the TGA website on 21 December 2017 at Consultation: Proposed Amendments to the Poisons Standard - ACCS, ACMS and Joint ACCS-ACMS meetings, March 2018.

Background information for cannabidiol, cannabis and tetrahydrocannabinols
Referred scheduling proposal

The delegate of the Secretary proposed an amendment to the Schedule 4 entry of cannabidiol, Schedule 8 entry of tetrahydrocannabinols and the Appendix K entries of cannabis and tetrahydrocannabinols (THCs) to clarify the meaning of the cannabidiol Schedule 4 entry in the Poisons Standard.

Scheduling application

The proposed amendments to the Poisons Standard are reflected below:

Schedule 4 CANNABIDIOL in preparations for therapeutic use containing 2 per cent or less of other cannabinoids found in cannabis in which in which:

  1. cannabidiol comprises at least 98 per cent of the total cannabinoid content of the preparation; and
  2. any other cannabinoids present are only those naturally found in cannabis, and are present only as unavoidable impurities in the cannabidiol component of the preparation.

Schedule 8

# TETRAHYDROCANNABINOLS when extracted from cannabis for human therapeutic use, when:

  1. included in products manufactured in accordance with the Narcotic Drugs Act 1967; and/or
  2. imported as therapeutic goods, or for use in therapeutic goods, for supply, in accordance with the Therapeutic Goods Act 1989; and/or
  3. in therapeutic goods supplied in accordance with the Therapeutic Goods Act 1989,
  4. except when:
    1. it is a product to which item 4, 8, 10, 11 or 12 of Schedule 5A to the Therapeutic Goods Regulations 1990 applies; or
    2. in hemp seed oil, containing 50 mg/kg or less of tetrahydrocannabinols when labelled with either of the following warning statements:
      1. Not for internal use; or
      2. Not to be taken; or
    3. separately specified in the NABIXIMOLS entry in this Schedule; or
    4. separately specified in Schedule 4.

Appendix K

CANNABIS except when included in Schedule 4.

(or CANNABIS in any form except the alkaloid cannabidiol)

TETRAHYDROCANNABINOLS except when included in Schedule 4.

(or TETRAHYDROCANNABINOLS in any form except the alkaloid cannabidiol).

The reasons for the proposed amendments are:

  • The current schedule entry for cannabidiol is causing ongoing confusion. This amendment seeks to clarify the schedule entry.
  • The proposed amendment is to further refine the scheduling delegate's final decision on cannabis and tetrahydrocannabinols and cannabidiol (published on 31 May 2017).
  • To specify that cannabidiol is not considered likely to cause sedation.
  • To identify cannabis and THCs as forming part of the 'other cannabinoid' component in the cannabidiol Schedule entry.
Scheduling status at time of referral

Cannabidiol was specifically listed in Schedules 4 and 8 of the Poisons Standard October 2017 as follows:

Schedule 4

CANNABIDIOL in preparations for therapeutic use containing 2 per cent or less of other cannabinoids found in cannabis.

Schedule 8

# NABIXIMOLS (botanical extract of Cannabis sativa which includes the following cannabinoids: tetrahydrocannabinols, cannabidiol, cannabinol, cannabigerol, cannabichromene, cannabidiolic acid, tetrahydrocannabinolic acids, tetrahydrocannabivarol, and cannabidivarol, where tetrahydrocannabinols and cannabidiol (in approximately equal proportions) comprise not less than 90 per cent of the total cannabinoid content) in a buccal spray for human therapeutic use.

Index

CANNABIDIOL
cross reference: CANNABIS, NABIXIMOLS

Schedule 4

Related compounds cannabis and tetrahydrocannabinols are listed in Schedules 8 and 9 and Appendices D and K of the Poisons Standard as follows:

Schedule 8

# CANNABIS (including seeds, extracts, resins and the plant, and any part of the plant) when prepared or packed for human therapeutic use, when:

  1. cultivated or produced, or in products manufactured[10], in accordance with the Narcotic Drugs Act 1967; and/or
  2. for use in products manufactured in accordance with the Narcotic Drugs Act 1967; and/or
  3. imported as therapeutic goods, or for use in therapeutic goods, for supply, in accordance with the Therapeutic Goods Act 1989; and/or
  4. in therapeutic goods supplied in accordance with the Therapeutic Goods Act 1989,
  5. except when:
    1. it is a product to which item 4, 8, 10, 11 or 12 of Schedule 5A to the Therapeutic Goods Regulations 1990 applies; or
    2. separately specified in Schedule 4; or
    3. separately specified in the NABIXIMOLS entry in this Schedule; or
    4. in hemp seed oil for purposes other than internal human therapeutic use containing 50 mg/kg or less of cannabinoids.

# TETRAHYDROCANNABINOLS when extracted from cannabis for human therapeutic use, when:

  1. included in products manufactured in accordance with the Narcotic Drugs Act 1967; and/or
  2. imported as therapeutic goods, or for use in therapeutic goods, for supply, in accordance with the Therapeutic Goods Act 1989; and/or
  3. in therapeutic goods supplied in accordance with the Therapeutic Goods Act 1989,
  4. except when:
    1. it is in a product to which item 4, 8, 10, 11 or 12 of Schedule 5A to the Therapeutic Goods Regulations 1990 applies; or
    2. in hemp seed oil, containing 50 mg/kg or less of tetrahydrocannabinols when labelled with either of the following warning statements:
      1. Not for internal use; or
      2. Not to be taken; or
    3. in products for purposes other than for internal human use containing 50 mg/kg or less of tetrahydrocannabinols; or
    4. separately specified in the NABIXIMOLS entry in this Schedule.

Schedule 9

CANNABIS (including seeds, extracts, resins, and the plant and any part of the plant when packed or prepared), except:

  1. when separately specified in these Schedules; or
  2. processed hemp fibre containing 0.1 per cent or less of tetrahydrocannabinols and hemp fibre products manufactured from such fibre; or
  3. in hemp seed oil for purposes other than internal human use containing 50 mg/kg or less of cannabinoids.

TETRAHYDROCANNABINOLS and their alkyl homologues, except:

  1. when included in Schedule 4 or Schedule 8; or
  2. processed hemp fibre containing 0.1 per cent or less of tetrahydrocannabinols, and hemp fibre products manufactured from such fibre
  3. in hemp seed oil, containing 50 mg/kg or less of tetrahydrocannabinols when labelled with either of the following warning statements:
    1. Not for internal use; or
    2. Not to be taken; or
  4. in products for purposes other than internal human use containing 50 mg/kg or less of tetrahydrocannabinols.

Appendix D, Item 1

CANNABIS for human use.

TETRAHYDROCANNABINOLS for human use.

Appendix K

CANNABIS

TETRAHYDROCANNABINOLS

Pending scheduling changes as of 1 June 2018

Following a previous final decision made by a delegate of the Secretary and published on the TGA website on 31 May 2017, on 1 June 2018, the abovementioned entries will be amended to read as follows:

Schedule 9

CANNABIS (including seeds, extracts, resins, and the plant and any part of the plant when packed or prepared), except:

  1. when separately specified in these Schedules; or
  2. processed hemp fibre containing 0.1 per cent or less of tetrahydrocannabinols, and hemp fibre products manufactured from such fibre; or
  3. in hemp seed oil for purposes other than internal human use containing 50 mg/kg or less of total cannabinoids, including 20 mg/kg or less of tetrahydrocannabinols, when labelled with either of the following warning statements:
    1. Not for internal use; or
    2. Not to be taken.

Schedule 8

# CANNABIS (including seeds, extracts, resins and the plant, and any part of the plant) when prepared or packed for human therapeutic use, when:

  1. cultivated or produced, or in products manufactured[11], in accordance with the Narcotic Drugs Act 1967; and/or
  2. for use in products manufactured in accordance with the Narcotic Drugs Act 1967; and/or
  3. imported as therapeutic goods, or for use in therapeutic goods, for supply, in accordance with the Therapeutic Goods Act 1989; and/or
  4. in therapeutic goods supplied in accordance with the Therapeutic Goods Act 1989,
  5. except when:
    1. it is a product to which item 4, 8, 10, 11 or 12 of Schedule 5A to the Therapeutic Goods Regulations 1990 applies; or
    2. separately specified in Schedule 4; or
    3. separately specified in the NABIXIMOLS entry in this Schedule.

Schedule 9

TETRAHYDROCANNABINOLS and their alkyl homologues, except:

  1. when included in Schedule 4 or Schedule 8; or
  2. processed hemp fibre containing 0.1 per cent or less of tetrahydrocannabinols, and hemp fibre products manufactured from such fibre; or
  3. in hemp seed oil for purposes other than internal human use containing 50 mg/kg or less of total cannabinoids, including 20 mg/kg or less of tetrahydrocannabinols, when labelled with either of the following warning statements:
    1. Not for internal use; or
    2. Not to be taken.

Schedule 8

# TETRAHYDROCANNABINOLS when extracted from cannabis for human therapeutic use, when:

  1. included in products manufactured in accordance with the Narcotic Drugs Act 1967; and/or
  2. imported as therapeutic goods, or for use in therapeutic goods, for supply, in accordance with the Therapeutic Goods Act 1989; and/or
  3. in therapeutic goods supplied in accordance with the Therapeutic Goods Act 1989,
  4. except when:
    1. it is in a product to which item 4, 8, 10, 11 or 12 of Schedule 5A to the Therapeutic Goods Regulations 1990 applies; or
    2. separately specified in the NABIXIMOLS entry in this Schedule.

Schedule 4

CANNABIDIOL in preparations for therapeutic use containing 2 per cent or less of total other cannabinoids found in cannabis.

Index

CANNABICHROMENE
cross reference: NABIXIMOLS, CANNABIS, TETRAHYDROCANNABINOLS

CANNABIDIOL
cross reference: NABIXIMOLS, CANNABIS, TETRAHYDROCANNABINOLS

CANNABIDIOLIC ACID
cross reference: NABIXIMOLS, CANNABIS, TETRAHYDROCANNABINOLS

CANNABIDIVAROL
cross reference: NABIXIMOLS, CANNABIS, TETRAHYDROCANNABINOLS

CANNABIGEROL
cross reference: NABIXIMOLS, CANNABIS, TETRAHYDROCANNABINOLS

CANNABINOIDS
cross reference: NABIXIMOLS, CANNABIS, TETRAHYDROCANNABINOLS

CANNABINOL
cross reference: NABIXIMOLS, CANNABIS, TETRAHYDROCANNABINOLS

CANNABIS
cross reference: CANNABIS SATIVA, HEMP, HEMP SEED OIL, TETRAHYDROCANNABINOLS

TETRAHYDROCANNABINOLIC ACID
cross reference: NABIXIMOLS, TETRAHYDROCANNABINOLS, CANNABIS

TETRAHYDROCANNABINOLS
cross reference: CANNABIS, HEMP SEED OIL, NABIXIMOLS

TETRAHYDROCANNABIDIVAROL
cross reference: NABIXIMOLS, TETRAHYDROCANNABINOLS, CANNABIS

Scheduling history

In February 2009, cannabidiol (CBD) was discussed by the National Drug and Poisons Scheduling Committee (NDPSC) as a part of a consideration of THC and a THC containing product, which led to the creation of the nabiximols entry (June and October 2009).

While the focus of the February 2009 meeting item was on the classification of THC, a number of public submissions received were regarding the availability of the product which contains both THC and CBD. It was noted that it was difficult to give approval to special access scheme applications for medications containing CBD as it was considered a Schedule 9 substance.

However, access would be granted if CBD was placed in Schedule 8 for therapeutic use. This scheduling consideration was to be discussed at the June 2009 meeting.

In June 2009, following further research regarding the product, the NDPSC decided that a Schedule 8 entry needed to exempt only the formulation from Schedule 9 rather than the 'substance' and therefore created the Schedule 8 entry for Cannabis sativa extract, listing the individual cannabidiols and restricting its presentation to buccal sprays for therapeutic use.

In October 2009, the NDPSC considered the scheduling of nabiximols after it was established that the United States of America Adopted Names Council had designated 'nabiximols' as the approved non-proprietary name for an extract of Cannabis sativa. This extract contained THC and CBD as major components and related cannabinoids and non-cannabinoid components alpha- and trans-caryophyllenes as minor components (i.e. the specific THC and CBD formulation considered appropriate for inclusion in Schedule 8 by the June 2009 meeting). As a result of this change in the US, the NDPSC amended Schedule 8 to refer to nabiximols instead of Cannabis sativa.

In November 2014, the ACMS considered the scheduling of cannabidiol. The committee recommended to the scheduling delegate that cannabidiol, including extracts of Cannabis sativa, and including preparations of up to 2% of cannabinoids, including cannabidivarin (CBDV) for therapeutic use, be included in Schedule 4. The reasons for the recommendation included:

  • The condition that cannabidiol treats (the therapeutic use) requires diagnosis, management and monitoring under an appropriate medical practitioner.
  • Cannabidiol has a safety profile which is consistent with a Schedule 4 listing.
  • There is low risk of misuse or abuse as cannabidiol does not possess psychoactive properties.

In May 2016, after extensive consultation, the scheduling delegate agreed with the committee recommendations and provided further reasons and clarification of the decision that included:

  • The schedule entry needs to acknowledge that there is no pure form of cannabidiol currently available. However, low levels of impurities found in some cannabidiol products are not clinically significant and the scheduling entry should reflect this by allowing cannabinoids up to 2 %.
  • The entry allows for, but does not specify, any particular non-active cannabis impurity/ies to be within the 'up to 2%'.
  • The substances that comprise the 'up to 2%' must be substances found in cannabis. They cannot be synthetic cannabinoids.
  • The entry does not preclude the cannabidiol and/or any other cannabinoids being derived from natural sources or made artificially, consistent with the interpretation of the schedules.
  • An amendment to Appendix D was not supported as the criteria are not met. It is considered that it is the medical condition for which CBD may be used which requires treatment by a specialist. Cannabidiol itself has no particular attributes that require it to be included in Appendix D. Scope of practice will ensure the appropriate prescribing of cannabidiol, rather than scheduling.

As a result, a Schedule 4 entry for cannabidiol was created, and the Schedule 9 entry for THC and their alkyl homologues was amended to exempt the new Schedule 4 entry for cannabidiol.

In November 2016, the Joint Advisory Committee on Medicines and Chemicals Scheduling (Joint ACMS-ACCS) further considered cannabidiol to improve the clarity of the entry with regards to the component cannabinoids found in cannabis. On 31 May 2017 the final decision and reasons was published. Amendments were made to the Schedule 8 and 9 entries for cannabis and tetrahydrocannabinols, and the Schedule 4 entry for cannabidiol. The amendment to the cannabidiol Schedule 4 entry (inclusion of the word 'total' in relation to the other cannabinoids found in cannabis) was made to improve the clarity of the cannabidiol entry.

Australian regulations

On the Australian Register of Therapeutic Goods (ARTG), there is one product containing cannabidiol which has been approved for export only.

There is no reference to cannabidiol, cannabis or THC in the Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2018 as they are scheduled ingredients, and are not eligible for use in ARTG listed medicines.

According to the TGA Ingredient Database, cannabidiol is available for use as an Active Ingredient in Export Only and Prescription Medicines, and there is no reference to cannabis or THC.

In the last 30 years, in the Database of Adverse Events Notification (DAEN) - Medicines:

  • There have been 2 reported cases of adverse events related to cannabidiol: 1 case with a single suspected medicine and no cases where death was a reported outcome;
  • There have been 77 reported cases of adverse events related to cannabis: 77 cases with a single suspected medicine and 1 case where death was a reported outcome; and
  • There have been no reported cases of adverse events related to THC.
International regulations
  • New Zealand: Cannabidiol is classified as a Class B1 Controlled drug and Prescription Medicine and cannabis and THC are classified as a Class C1 Controlled Drugs.
  • United States of America (USA): In the USA, 13 states have statutes recognising CBD for medical use, 23 states have statutes recognising 'medicinal marijuana'.
  • European Union: The European Medicines Agency approved CBD for certain medical uses (GvHD, Dravet syndrome, Lennox-Gastaut syndrome, perinatal asphyxia) and THC for the treatment of pain and spasticity.
  • Canada: Cannabidiol and THC are classified as a Schedule II medicine.
Substance summary

Cannabis

Cannabis is a term used to describe a range of varieties of the Cannabis genus. The Cannabis plant produces a resin containing compounds called cannabinoids. Some cannabinoids possess psychoactive properties.

Cannabis contains about 60 cannabinoids, of which the main active constituent is delta-9-tetrahydrocannabinol. Delta-9-tetrahydrocannabinol reportedly has anti-emetic properties, and has been associated with claims relating to use for the control of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional anti-emetics. Another active cannabinoid present in Cannabis is cannabidiol, which is associated with claims relating to use as an analgesic, anticonvulsant, muscle relaxant, anxiolytic, neuroprotective, anti-oxidant and anti-psychotic.

Nabiximols is a specific extract of Cannabis sativa which contains a range of cannabinoids, of which THC and cannabidiol, in approximately equal proportions, comprise not less than 90% of the total cannabinoid content. Nabiximols are registered for use in Australia as a buccal spray preparation as an adjunctive treatment for the symptomatic relief of neuropathic pain associated with multiple sclerosis in adults.

Nabilone is a synthetic cannabinoid used as an anti-emetic in the treatment of nausea and vomiting caused by chemotherapy and also for patients who are not responsive to conventional anti-emetic treatments.

Hemp seed oil as defined in Part 1 Interpretation, Paragraph (1) of the Poisons Standard is the oil obtained by cold expression from the ripened fruits (seeds) of Cannabis sativa. Hemp oil is distinct from hemp seed oil and includes extracts from the flowering tops or leaves or any other part of the Cannabis plant other than the ripened fruit (seeds).

Information in the public domain, including websites and literature articles[12] report cannabinoids are not synthesised within the hemp seed. However, traces of delta-9-tetrahydrocannabinol and cannabidiol contamination of the seed may occur due to residual contamination of the outside of the seed coat, even under good agricultural/manufacturing practice. Rigorous cleaning methods, including washing, sieving and shelling, may help reduce or remove any cannabinoid contamination of seeds.

Reported gas chromatography (GC) analytical composition data of hemp seed oil (variety Fedora-19) from Leizer, et al., (2000) includes significant portions of polyunsaturated fatty acids such as linoleic acid, oleic acid, stearic acid eichosanoic acids and palmitic acid, with more than 80% of the content being unsaturated fatty acids. Other trace compounds reported include Vitamin E (tocopherols), β sitosterol, and terpenes (e.g. myrcene and caryophyllene) and salicylates.

Given this information, hemp seed oil products should not contain significant amounts of cannabinoids. The presence of cannabinoids in hemp seed oil is considered to arise from either a contamination or adulteration, rather than to be naturally occurring.

Cannabidiol

Cannabidiol is a cannabinoid compound which occurs naturally in Cannabis sativa plants. The pharmacology of cannabidiol is complex and has been well characterised in vitro.

Some cannabinoid compounds work by binding to the cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2) receptors in the brain. Cannabidiol does not activate CB1 and CB2 receptors directly. However, it has effects on many other 'signalling' systems and can be considered a 'multi-target' drug. Some of the effects of cannabidiol may be attributed to inhibition of the inactivation of endocannabinoids, such as anandamide. Other effects may be related to the chemical properties of the compound as opposed to pharmacodynamic effects. For example, it is thought that the presence of two hydroxyl groups enables cannabidiol to have an anti-oxidant action.

There is evidence that cannabidiol affects serotonin receptors (5HT1A), adenosine uptake, nuclear receptors of the peroxisome proliferator-activated receptors (PPAR) family and other pharmacological targets. The pharmacological targets of cannabidiol include receptors, ion channels, enzymes and cellular uptake processes.

There are reports that cannabidiol possesses anti-proliferative, pro-apoptotic effects and inhibits cancer cell migration, adhesion and invasion. Evidence is also accumulating that there are positive effects of cannabidiol in the vasculature, where cannabidiol may induce vasorelaxation.

Information about the pharmacokinetics of the substance in humans is also accumulating. Oral absorption is slow and unpredictable relative to other routes of administration, possibly due to the chemical's poor water solubility. There is significant first pass metabolism where the concentration of ingested cannabidiol is greatly reduced before it is absorbed into systemic circulation, and the overall oral bioavailability may be as low as 6%. Other sources suggest an oral bioavailability of between 12 and 19%. Oromucosal and sublingual delivery, through sprays and lozenges, results in less variability with similar overall bioavailability.

The distribution of cannabidiol is governed by its high lipophilicity and there is rapid distribution to the brain, adipose tissue and other organs. It is also highly protein bound.

Like most cannabinoids, cannabidiol is extensively metabolised in the liver by cytochrome P450 enzymes, predominantly the CYP3A and CYP2C series. The terminal half-life is estimated to be 18-32 hours, although earlier work suggested a much shorter half-life of only 9 hours.

Table 1.2A: Chemical information of cannabidiol
Property Cannabidiol
CAS number 13956-29-1
Chemical structure Chemical structure of Cannabidiol
Molecular formula C21H30O2
Molecular weight 314.469 g/mol
IUPAC and/or common and/or other names 2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol (IUPAC)

Tetrahydrocannabinol

THC is one of at least 113 cannabinoids identified in cannabis and is the principal psychoactive constituent of cannabis.

The THC effects result from its partial agonist activity at the cannabinoid receptor CB1 located mainly in the central nervous system, and the CB2 receptor mainly expressed in cells of the immune system. The psychoactive effects of THC are primarily mediated by the activation of cannabinoid receptors, which result in a decrease in the concentration of the second messenger molecule cAMP through inhibition of adenylate cyclase.

Pre-meeting public submissions

One (1) public submission was received which opposed the proposal.

The main points provided in opposition of the amendment were:

  • The key area of confusion is in respect to the cannabidiol content of the preparation, versus its proportion to other cannabinoids. Interpretations have included 98% of the preparation must be cannabidiol in contrast to 98% of the total cannabinoids in the preparation must be cannabidiol.
  • The proposed Schedule 4 cannabidiol entry amendment introduces additional ambiguity, including:
    • The use of the word 'other' in point b implies that the cannabidiol itself may not be subject to the requirement of being 'naturally found in cannabis'; and
    • The introduction of the term 'unavoidable impurities' with regards to other cannabinoids present introduces ambiguity and subjectivity in what, under point a, had been a quantitative measure i.e. that cannabinoids other than cannabidiol can only represent up to 2% of the total cannabinoid content.
  • Although it is self-explanatory that tetrahydrocannabinol is a cannabinoid, it is not clear how or where tetrahydrocannabinols are 'included' or 'specified' in Schedule 4. This can be addressed by specifically making reference to tetrahydrocannabinol in the cannabidiol entry, and also by cross referencing tetrahydrocannabinols to cannabidiol in the Index of the Poisons Standard. This would assist in comprehension of the proposed amendments to the tetrahydrocannabinol entries in Appendix K and Schedule 8.

The public submission will be made available on the TGA website.

Summary of ACCS advice to the delegate

The committee recommended that the Schedule 4 entry for cannabidiol, the Schedule 8 entry for tetrahydrocannabinols and the Appendix K entries of tetrahydrocannabinols and cannabis be amended in the Poisons Standard as follows:

Schedule 4 - Amend Entry

CANNABIDIOL in preparations for therapeutic use containing 2 per cent or less of other cannabinoids found in cannabis where:

  1. cannabidiol comprises 98 per cent or more of the total cannabinoid content of the preparation; and
  2. any cannabinoids, other than cannabidiol, must be only those naturally found in cannabis and total 2 per cent or less of the cannabinoid content of the preparation.

Schedule 8 - Amend Entry

# TETRAHYDROCANNABINOLS when extracted from cannabis for human therapeutic use, when:

  1. included in products manufactured in accordance with the Narcotic Drugs Act 1967; and/or
  2. imported as therapeutic goods, or for use in therapeutic goods, for supply, in accordance with the Therapeutic Goods Act 1989; and/or
  3. in therapeutic goods supplied in accordance with the Therapeutic Goods Act 1989,
  4. except when:
    1. it is a product to which item 4, 8, 10, 11 or 12 of Schedule 5A to the Therapeutic Goods Regulations 1990 applies; or
    2. in hemp seed oil, containing 50 mg/kg or less of tetrahydrocannabinols when labelled with either of the following warning statements:
      1. Not for internal use; or
      2. Not to be taken; or
    3. separately specified in the NABIXIMOLS entry in this Schedule; or
    4. the alkaloid cannabidiol when included in Schedule 4.

Schedule 8 - Amend Entry

# CANNABIS (including seeds, extracts, resins and the plant, and any part of the plant) when prepared or packed for human therapeutic use, when:

  1. cultivated or produced, or in products manufactured[13], in accordance with the Narcotic Drugs Act 1967; and/or
  2. for use in products manufactured in accordance with the Narcotic Drugs Act 1967; and/or
  3. imported as therapeutic goods, or for use in therapeutic goods, for supply, in accordance with the Therapeutic Goods Act 1989; and/or
  4. d) in therapeutic goods supplied in accordance with the Therapeutic Goods Act 1989,
  5. except:
    1. when it is a product to which item 4, 8, 10, 11 or 12 of Schedule 5A to the Therapeutic Goods Regulations 1990 applies; or
    2. separately specified in Schedule 4 the alkaloid cannabidiol when included in Schedule 4; or
    3. when separately specified in the NABIXIMOLS entry in this Schedule; or
    4. when in hemp seed oil for purposes other than internal human therapeutic use containing 50 mg/kg or less of cannabinoids.

Appendix K - Amend Entry

CANNABIS except the alkaloid cannabidiol when included in Schedule 4.

TETRAHYDROCANNABINOLS except the alkaloid cannabidiol when included in Schedule 4.

The committee also recommended an implementation date of 1 October 2018.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice included:

  1. the risks and benefits of the use of a substance:
    • Benefit - clarity of entry meaning
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • See point (f).
  3. the toxicity of a substance:
    • See point (f).
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • See point (f).
  5. the potential for abuse of a substance:
    • See point (f).
  6. any other matters that the Secretary considers necessary to protect public health
    • This consideration is about clarification only and does not seek to change the original scheduling decisions in a substantive manner.
    • Clarification of these entries is necessary to prevent their inadvertent or deliberate misinterpretation resulting in harm through Schedule 8 products being treated as Schedule 4 medicines, including not obtaining State authority to prescribe, and increased potential for diversion/misuse because of less restrictive storage and recording requirements.
Delegate's considerations

In making this decision, I have considered the following:

  • Scheduling proposal;
  • ACMS advice;
  • Public submissions received;
  • Scheduling Policy Framework (SPF 2018); and
  • Section 52E(1) of the Therapeutic Goods Act 1989 in particular: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

Footnotes

  1. 'Cultivation', 'production' and 'manufacture' have the same meaning as in the Narcotic Drugs Act 1967
  2. Cultivation', 'production' and 'manufacture' have the same meaning as in the Narcotic Drugs Act 1967
  3. 'Cultivation', 'production' and 'manufacture' have the same meaning as in the Narcotic Drugs Act 1967
  4. P1042 - Low THC Hemp Seeds as Food and Leizer, C. et al., The Composition of Hemp Seed Oil and Its Potential as an Important Source of Nutrition (pdf,145kb), J. Nutraceuticals, Functional & Medical Foods 2000 2(4) 35 - 53
  5. 'Cultivation', 'production' and 'manufacture' have the same meaning as in the Narcotic Drugs Act 1967

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