Interim decisions on matters referred to an expert advisory committee: ACMS out-of-session November 2014

2. Scheduling proposals referred to the Out of Session November 2014 meeting of the Advisory Committee on Medicines Scheduling

2.1 Cannabidiol

Scheduling proposal

To create a new Schedule 4 entry for cannabidiol for therapeutic use with consideration of an Appendix D listing.

The delegate referred the proposal to the Advisory Committee on Medicines Scheduling (ACMS) for advice.

Substance summary

Cannabidiol is a cannabinoid compound which occurs naturally in Cannabis sativa plants. Cannabidiol has the chemical formula C21H30O2 and its CAS number is 13956-29-1. The pharmacology of cannabidiol is complex and has been well characterised in in-vitro environments.

Some cannabinoid compounds work by binding to the CB1 and 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. Its pharmacological targets include receptors, ion channels, enzymes and cellular uptake processes.

There are reports that cannabidiol possesses antiproliferative, 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 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.

Scheduling status

Cannabidiol is not currently specifically scheduled in the Poisons Standard.

As a constituent of cannabis, the substance would be captured by the entry for cannabis in Schedule 9.

However, cannabidiol may also be a constituent of hemp seed oil. Hemp seed oil is defined as the oil obtained by cold expression from the ripened fruits (seeds) of Cannabis sativa and is exempted from scheduling provided the oil contains 50 mg/kg or less of tetrahydrocannabinols and is labelled with the warning statement: "Not for internal use" or "Not to be taken".

Cannabidiol is also mentioned in the Schedule 8 entry for nabiximols. However, nabiximols is defined as containing a range of cannabinoids including a mixture of both Δ9-tetrahydrocannabinol (THC) and cannabidiol.

Schedule 9

CANNABIS except:

1. when separately specified in these Schedules; or
2. processed hemp fibre containing 0.1 per cent or less of tetrahydrocannabinol and products manufactured from such fibre.

Schedule 9

TETRAHYDROCANNABINOLS and their alkyl homologues except:

1. when separately specified in this Schedule;
2. when included in Schedule 8;
3. in hemp seed oil, containing 50 mg/kg or less of tetrahydrocannabinols when labelled with a warning statement:
   • Not for internal use; or
   • Not to be taken; or
4. in products for purposes other than internal human use containing 50 mg/kg or less of tetrahydrocannabinols.

Schedule 8

DRONABINOL (delta-9-tetrahydrocannabinol) when prepared and packed for therapeutic use

NABILONE

NABIXIMOLS (botanical extract of Cannabis sativa which includes the following cannabinoids: tetrahydrocannabinol, cannabidiol, cannabinol, cannabigerol, cannabichromene, cannabidiolic acid, tetrahydrocannabinolic acid, tetrahydrocannabivarol, and cannabidivarol, where tetrahydrocannabinol 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.

Scheduling history

Cannabidiol [CBD] has been discussed by the National Drug and Poisons Scheduling Committee (NDPSC) as a part of a consideration of tetrahydrocannabinols (THC) (February 2009) and the product Sativex^© which lead 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 Sativex^© which contains both THC and CBD. At that time, jurisdictional members noted that it was difficult to give approval to SAS 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.

Following further research regarding the Sativex^© product, the NDPSC decided at the June meeting the 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 it's presentation to buccal sprays for therapeutic use.

In October 2009, the NDPSC considered the scheduling of nabiximols, after it was established that the US Adopted Names Council had designated 'nabiximols' as the approved non-proprietary name for an extract of Cannabis sativa containing, as major components, THC+CBD, and as minor components, related cannabinoids and non-cannabinoid components alpha- and trans-caryophyllenes i.e. the specific THC+CBD formulation considered appropriate for inclusion in Schedule 8 by the June 2009 meeting. The June 2008 cannabis sativa extract Schedule 8 entry was therefore amended to nabiximols.

Pre-meeting public submissions

Thirty-five submissions were received with 10 supporting the proposal, 8 with no comment on the proposal and 17 rejecting the proposal requesting that cannabis is scheduled instead. Of the eight, no comment submissions, a majority of those suggested the rescheduling of cannabis in Schedule 4.

ACMS advice to the delegate

The ACMS recommended 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 ACMS recommended an implementation date of 1 June 2015.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: 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; and e) the potential for abuse of a substance.

The reasons for the recommendation comprised the following:

• 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.

Delegate's considerations

The delegate considered the following in regards to this proposal:

• Scheduling proposal;
• Public submissions received;
• ACMS advice;
• Section 52E of the Therapeutic Goods Act 1989;
• Scheduling factors¹³;
• Other relevant information.

Delegate's interim decision

The delegate's interim decision is

• To include in Schedule 4
  • CANNABIDIOL in preparations for therapeutic use except when containing more than 2 per cent of other cannabinoids found in cannabis.
  • To amend the Schedule 9 entry for TETRAHYDROCANNABINOLS and their alkyl homologues exception (b) to:
    • when included in Schedule 4 and Schedule 8

The proposed implementation date is 1 June 2015.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: 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; and e) the potential for abuse of a substance.

The reasons for the recommendation comprised the following:

• 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.
• 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.
• Appendix D is 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 requires it to be included in Appendix D. Scope of practice will ensure the appropriate prescribing of cannabidiol rather than scheduling.

Scheduling proposal

Schedule 4 - New entry

CANNABIDIOL in preparations for therapeutic use except when containing more than 2 per cent of other cannabinoids found in cannabis.

Schedule 9 - Amended entry

TETRAHYDROCANNABINOLS and their alkyl homologues except:

1. when separately specified in this Schedule;
2. when included in Schedule 4 and Schedule 8;
3. in hemp seed oil, containing 50 mg/kg or less of tetrahydrocannabinols when labelled with a warning statement:
   • Not for internal use; or
   • Not to be taken; or
4. in products for purposes other than internal human use containing 50 mg/kg or less of tetrahydrocannabinols.

Footnotes

• ¹³ Scheduling Policy Framework for Medicines and Chemicals (SPF, 2010)