1.5 Cannabidiol and tetrahydrocannabinols (THCs)

1. Advisory Committee on Medicines Scheduling (ACMS #24)

On this page: Delegate's interim decision | Delegate's considerations | Scheduling proposal | Background information for cannabidiol and tetrahydrocannabinols

Delegate's interim decision

Delegate's considerations

The delegate considered the following in regards to this interim decision:

• The application to amend the current Poisons Standard with respect to cannabidiol and tetrahydrocannabinols;
• The advice received from the Advisory Committee on Medicines Scheduling (ACMS#24);
• The public submissions received before the first closing date;
• The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018); and
• Section 52E of the Therapeutic Goods Act 1989, in particular: (a) the 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; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (e) the potential for abuse of a substance.

Scheduling proposal

The pre-meeting scheduling proposal was published on the TGA website on 12 April 2018 at Consultation: Proposed amendments to the Poisons Standard being referred to the June 2018 meetings of the ACCS, ACMS and Joint ACCS/ACMS.

Background information for cannabidiol and tetrahydrocannabinols

In this section: Delegate's referral to ACMS | Applicant's scheduling proposal and reasons | Current scheduling status | Scheduling history | Australian regulations | International regulations | Substance summary | Pre-meeting public submissions | ACMS advice

Delegate's referral to ACMS

An application was submitted to amend the Poisons Standard with respect to cannabidiol and tetrahydrocannabinols (THCs). The application proposed to amend the Schedule 4 entry for cannabidiol.

Applicant's scheduling proposal and reasons

The applicant's proposed amendments to the Poisons Standard were:

The applicant's reasons for the proposal were:

• The applicant was advised by the WA Health Department that one of their products would come under Schedule 8 ('unless 98% of the total cannabinoids in the preparation are cannabidiol, it is in Schedule 8. In other words, the total amount of cannabinoids that are not cannabidiol would need to be 1:50 before the preparation would meet the Schedule 4 entry').
• The applicant argues that the decision to classify the product is erroneous since it compares the strength of one ingredient to another which is flawed. Classifying by using absolute weight per volume (%w/v) is the standard method of rating pharmaceutical strength and gives a true indication of the amount of THC. The product (1 mg THC/mL) contains low levels of THC. To classify it in the same schedule as the much higher strengths of 10 mg THC/mL and 18 mg THC/mL is confusing to prescribers.
• The application is based on the low harm/misuse potential of medicinal cannabis products and of the erroneous current scheduling classification comparing one cannabinoid to another rather than by %w/v (of the product).
• This scheduling application is in the public interest. Medicinal cannabis prescriptions are monitored closely by the TGA. Each prescription requires approval via the Special Access Scheme (SAS) category B. In some cases, further state approval may be needed. All applications are subject to a series of patient monitoring and after care. There are 3 strengths of this medication, the other two are Schedule 8 and re-classification is sought of the weakest strength to Schedule 4.
• There is an extremely low risk of overdosing on the product oil due to the provision of an accurate volumetric measuring device and clear dosing instructions. Furthermore, it should be noted that this extremely low risk would be the same with a 1:50 oil, which would be included in Schedule 4 based on its relative concentration of cannabinoids. Compared to the 1:20 oil, it would have the same concentration of THC and a higher CBD concentration (50 mg/mL).
• The risk of diversion for recreational use is insignificant with the product based on:
  • Inability to concentrate the product;
  • The olive oil carrier cannot be smoked or vaporised;
  • The amount of oil that would need to be ingested to get any possible recreational effect is clearly unattractive;
  • The total amount of 60 mg of THC per bottle of the product oil is below typical amounts ingested by recreational users;
  • CBD is a THC agonist and would moderate any effect; and
  • Oral or sublingual THC gives lower blood levels over a longer period compared to smoked cannabis.
• Compared with other products legally available in Australia (including the 18:0 and 10:10 oils), the product oil 1:20 is an unreasonably expensive and clearly unattractive option to access THC for recreational purposes. The current retail price of the product is $350 per 60 mL bottle.

• Under the federal TGA system TGO93: (9)

  '...are taken to be active ingredients for the purposes of this order (whether or not those ingredients are specified, disclosed, purported or notified to the Secretary to be active ingredients):

  (a) any tetrahydrocannabinol present in a medicinal cannabis product, the quantity or proportion of which (together with any corresponding acid) is greater than or equal to 1.0% w/w or w/v of the product'

• Interpreting the THC content in the three product oils based on the above information:
  • The 1:20 oil: 1.0 mg/mL, hence 0.1 % w/v THC should be in Schedule 4 (contains 20.0 mg/mL CBD or 2.0 % w/v, hence regarded as CBD);
  • The 10:10 oil: 9.8 mg/mL, hence 1.0 % w/v THC due to rounding (closer than 0.9 %) should be in Schedule 8; and
  • The 18:1 oil: 18.3 mg/mL, hence 1.8 % w/v THC should be in Schedule 8.
• Using an absolute limit on other cannabinoids in cannabidiol preparations is more appropriate from a patient safety perspective. It will limit psychotropic amounts of THC in a final preparation, which the current scheduling does not.

Current scheduling status

Cannabidiol

Cannabidiol is specifically listed in Schedules 4 and 8 of the Poisons Standard as follows:

THC

THC is specifically listed in Schedules 8 and 9 and Appendices D and K of the Poisons Standard as follows:

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 the product nabiximols, 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 the nabiximols 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 nabiximols 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). The Cannabis sativa extract Schedule 8 entry was amended to nabiximols.

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.
• 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 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 Chemicals Scheduling-ACMS further considered cannabidiol to improve the clarity of the entry with regards to the component cannabinoids found in cannabis. A final decision was made to improve the clarity of the cannabidiol entry on 31 May 2017, by including the word 'total' in relation to the other cannabinoids found in cannabis.

In March 2018, the ACMS provided advice to the delegate on a proposal to amend the Schedule 4 entry of cannabidiol, Schedule 8 entry of THCs and the Appendix K entries of cannabis and THCs to clarify the meaning of the cannabidiol Schedule 4 entry. The decision on this proposal is still pending.

Australian regulations

On the Australian Register of Therapeutic Goods (ARTG), there is one product containing cannabidiol for export only, and no products THC.

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 THC.

In the last 30 years, in the Database of Adverse Events Notification (DAEN) - Medicines there have been no reported cases of adverse events related to cannabidiol or THC.

International regulations

• New Zealand: Cannabidiol is classified as a Class B1 Controlled drug and Prescription Medicine and THC is 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^[39] 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 in vitro environments.

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 1.5: Chemical information of cannabidiol

Property	Cannabidiol
CAS number	13956-29-1
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)
Chemical structure
Molecular formula	C21H30O2
Molecular weight	314.5 g/mol

Tetrahydrocannabinol

THC is one of at least 113 cannabinoids identified in cannabis and is 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

Eight (8) public submissions were received before the first closing date in response to an invitation published on 12 April 2018 under regulation 42ZCZK of the Regulations. Two (2) of the submissions were in support of the proposed amendments to the Poisons Standard, one (1) in conditional support with amendments to the proposal, and two (2) that opposed the proposal. Three (3) of the submissions stated their opposition to the proposed amendments to the Poisons Standard but appeared to have misunderstood the applicant's proposal.

The main points provided in support of the amendment were:

• The proposed changes helpfully clarify the current industry confusion around cannabidiol scheduling. The changes do not alter the current public health risk and benefit calculation associated with medicinal cannabis or influence other matters raised in that section.
• The proposal would be a big step forward in legitimising medicinal cannabis as a viable medical treatment option for doctors and patients in Australia, especially considering the clinical justifications available for the use of cannabidiol-dominant products in a wide range of conditions.
• The wording in the current Schedule 4 entry for cannabidiol has meant that any preparation containing cannabidiol as an ingredient in less than 98% purity would be restricted to supply as a Schedule 8 medicine, regardless of the concentration of the ingredient in the product. The proposed change would broaden the scope of products that would fall into Schedule 4. If implemented, the proposed change will mean that cannabidiol dominant products containing other cannabinoids would fall into Schedule 4 as long as the concentration in the product of total cannabinoids other than cannabidiol does not exceed 1% w/v.
• From a scientific and clinical standpoint, this proposal is reasonable considering the favourable side-effect profiles of cannabidiol-dominant products, which justifies their designation as Schedule 4 medicines.
• The broadening of the scope of products that would fall into Schedule 4 will make access to medicinal cannabis products simpler for patients in need, owing to the less stringent state-based Schedule 4 requirements compared with the onerous Schedule 8 authorisations and dispensing protocols that doctors and pharmacists currently have to comply with for these products.
• Amendments suggested include:
  • "CANNABIDIOL in preparations for therapeutic use where tetrahydrocannabinoids comprise no more than 1% w/v, and other cannabinoids found in cannabis comprise no more than 2% w/v".
    • This suggested amendment will ensure that any given preparation will contain no more than 1% THC w/v, but may also contain other cannabinoids naturally present in the plant (as whole-plant extraction preparations will likely contain other cannabinoids in addition to THC).
  • "CANNABIDIOL in preparations for therapeutic where other cannabinoids found in cannabis comprise no more than 2% w/v or w/w of the preparation and of these other cannabinoids, tetrahydrocannabinol comprises no more than 1 % w/v or w/w of the final preparation."
    • The proposed limit in practice results in a much lower permitted actual THC content than 1.0% w/v or w/w. This is because all other cannabinoids present in the cannabidiol preparation must also be included in calculating the 1.0% limit. An alternative definition is proposed which allows for the presence of other cannabinoids, such that all cannabinoids (including THC) in total comprise up to 2.0% of the final preparation.
    • The current proposed definition only refers to w/v, whereas - consistent with TGO93 - for certain products, a w/w calculation (as an alternative) would be more appropriate.

The main points provided in opposition of the amendment were:

• The proposed amendments referred by the delegate for consideration by the ACMS at the March 2018 meeting provided far more clarity than this latest proposal.
• Amendments suggested include:

  • 'CANNABIDIOL in preparations for therapeutic use in which:

    1. cannabidiol (together with any corresponding acid) comprises at least 98 per cent of the total cannabinoid content of the preparation; and
    2. any cannabinoids present are only those naturally found in cannabis.'

    Point a) with the proposed addition adequately addresses the levels of all other cannabinoids present in a cannabidiol preparation. It would assist clarity to explicitly state that tetrahydrocannabinol may be included in the 'total cannabinoid content' within the levels stipulated under the CANNABIDIOL entry and further, by cross referencing tetrahydrocannabinol to cannabidiol in the Index of the Poisons Standard.

    In relation to point b) we suggest deleting 'dealing with unavoidable impurities'.

• Slight modification of the 21 December 2017 wording released for consultation would be the preferred wording:

  • 'CANNABIDIOL in preparations for therapeutic use in which:

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

    Point a) adequately addresses the levels of all other cannabinoids present in a cannabidiol preparation. It would assist clarity to both explicitly state that tetrahydrocannabinol may be included in the 'total cannabinoid content' within the levels stipulated under the CANNABIDIOL entry and to cross reference tetrahydrocannabinol to cannabidiol in the Index of the Poisons Standard.

The main points provided in opposition but appear to have misunderstood the amendment were:

• The World Health Organisation has determined that CBD is safe and should not be scheduled under either of the two international treaties - the Single Convention on Narcotic Drugs 1961 and the Convention on Psychotropic Substances 1971.^[40]
• CBD and THC are completely different substances and need to be regulated separate from one another. CBD does not require such strict regulation as it is non-toxic and non-addictive.^[41] Its safety has been demonstrated in multiple clinical studies.^[42]
• CBD is used globally to treat many conditions, most notably intractable epilepsy (Dravet's Syndrome). There are wider benefits in treating chronic pain and in palliative care for cancer patients.
• CBD is proving effective in combating the current abuse of opioids, where addiction and death are commonplace. In US jurisdictions where medicinal cannabis is available, prescriptions for opioids have fallen by as much as 25%.^[43] This has negative implications for Australia as it is a major supplier to the opioid industry and derives some $300 million per year from the sale of raw materials for drugs. Future export shortfalls can be more than covered by the Australian medicinal cannabis industry.
• In view of the acceptance that CBD is not a threat to health, lowering the accepted concentration levels is incongruous. The World Anti-Doping Agency (WADA) is one of the most stringent organisations in identifying substances that are either harmful or behaviour altering. In 2017, WADA removed CBD from the banned list whilst continuing to ban THC. This was in response to that fact that many athletes use CBD as an anti-inflammatory.^[44]
• Anecdotal evidence of efficacy of CBD.^[45] CBD is used globally in treating numerous conditions, for example, Chemotherapy induced nausea and vomiting and epilepsy.^{[46],[47],[48],[49]}
• CBD oil is safe to use as a dietary supplement. The Australian New Zealand Food Standards recognises that CBD only has a therapeutic effect if taking more than 120 mg/day.

ACMS advice

The committee recommends that the current scheduling of cannabidiol remains appropriate.

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; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (e) the potential for abuse of a substance.

The reasons for the advice included:

1. risks and benefits of the use of a substance:
   • No additional information provided on risks and benefits of THC and other non-CBD cannabinoids to justify their down-scheduling.
   • THC and selected other cannabinoids but not CBD are psychoactive.
   • Cannabinoids may have benefits in a range of indications.
2. the dosage, formulation, labelling, packaging and presentation of a substance:
   • There are a diverse range of formulations being developed containing a range of cannabinoid concentrations.
   • The Schedule 4 entry for cannabidiol needs to define products for which the CBD is the predominant active compound and as such is likely to limit the ability to consume psychoactive THC doses from that product.
3. the potential for abuse of a substance:
   • Cannabis and its preparations and especially products containing THC are subject to abuse.