2.1 Amygdalin and hydrocyanic acid

2. Interim decisions on proposed amendments referred to the Advisory Committee on Medicines Scheduling (ACMS #32, November 2020)

2.1 Interim decision in relation to amygdalin and hydrocyanic acid

Interim decision

Pursuant to regulation 42ZCZN of the Regulations, a Delegate of the Secretary has, in relation to the proposed amendment, made an interim decision not to amend the current Poisons Standard in relation to amygdalin and hydrocyanic acid.

Materials considered

In making this interim decision, the Delegate considered the following material:

• The application to amend the current Poisons Standard with respect to amygdalin and hydrocyanic acid;
• The 129 public submissions - external site, including two written submissions, received in response to the pre-meeting consultation under regulation 42ZCZK of the Regulations;
• The advice received from the Meeting of the Advisory Committee on Medicines Scheduling (ACMS #32);
• Subsection 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; and (e) the potential for abuse of a substance;
• The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018);
• The Scheduling handbook: Guidance for amending the Poisons Standard; and
• An external expert evaluation (pdf,682kb) of the private application.

Summary of ACMS advice to the Delegate

The Committee recommended that the current scheduling for amygdalin and hydrocyanic acid remains appropriate.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (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; and (e) the potential for abuse of a substance,

The reasons for the advice included:

1. the risks and benefits of the use of a substance:
   • Risks
     • High risk of cyanide toxicity with high variability.
   • Benefits
     • Limited evidence of benefit, other than increased access.
2. the purposes for which a substance is to be used and the extent of use of a substance:
   • Amygdalin and hydrocyanic acid (released by the natural degradation of amygdalin by enzymes in the plant preparation) occur naturally in plants used in traditional Chinese medicines for health conditions described within the philosophy (theory, pathology, diagnosis, treatment and herbal pharmacology principles) of traditional Chinese medicine. Legitimate purpose of use not well defined.
   • The substance is currently prohibited and the extent of use is unknown.
3. the toxicity of a substance:
   • The toxicity of the substance is well established. Amygdalin exhibits considerable toxicity due to the production of hydrocyanic acid following hydrolysis.
   • Complete degradation of 1g amygdalin releases 59mg of hydrocyanic acid (5mg amygdalin would be equivalent to 0.3mg HCN). Cyanide is readily absorbed reaching maximum blood levels within minutes and is distributed to all organs. The primary mode of action by which cyanide exerts acute toxicity is the inhibition of oxidative phosphorylation.
   • In humans, the lethal oral dose of HCN is reported to be 0.5–3.5 mg/kg body weight. A level of 0.5 mg/L (approximately 20 micromolar) of cyanide in blood is cited in the literature as a toxicity threshold in humans. A series of poisoning cases are reported from ingestion of preparations containing amygdalin and bitter apricot kernels. In adults, 20 or more kernels were reported to be toxic while the corresponding number in children was five.
   • Toxicity is dose-related but also exhibits considerable inter-individual variability.
   • The independent evaluation report requested by the delegate includes 5 case reports of toxicity in adults with daily oral amygdalin/laetrile doses ranging from approximately 420mg to 1.5g.
4. the dosage, formulation, labelling, packaging and presentation of a substance:
   • Traditional Chinese medicines uses various oral dose forms; no specific products were described in the application.
   • Limiting amygdalin to being a natural component of traditional Chinese medicines for oral use by adults does not provide sufficient regulatory safety.
5. the potential for abuse of a substance:
   • Amygdalin has been inappropriately promoted and used as an alternative cancer treatment. Claims for use in treating or preventing cancer are unproven.

Reasons for the interim decision (including findings on material questions of fact)

I have made an interim decision to retain the scheduling of amygdalin and hydrocyanic acid in the current Poisons Standard. This decision is to not down-schedule amygdalin as a natural component in Traditional Chinese Medicines (TCM) for oral use in adults from Schedule 10 to Schedule 4, make amygdalin unscheduled when the maximum recommended daily dose is ≤5 mg amygdalin; nor to make hydrocyanic acid unscheduled for therapeutic use when present as a natural component of amygdalin in TCM for oral use in adults. The detailed reasons for my interim decision are set out below.

Amygdalin is a naturally occurring cyanogenic glycoside compound converted into hydrocyanic acid in the gut. Hydrocyanic acid (cyanide) halts cellular respiration leading to nausea, fever, headaches, insomnia, thirst, lethargy, nervousness, joint and muscle aches and pains, falling blood pressure, and in some cases, death^[1]. The toxicity of amygdalin is highly variable and influenced by numerous factors, including other ingested plants or nutrients (e.g. plant enzymes or ascorbic acid), vitamin B12 and individual gut flora^[2].

I consider that amygdalin should not be down-scheduled from its current listing in Schedule 10. The history of persistent misuse of amygdalin for the treatment of cancer is of relevance to my consideration^[3]. Amygdalin has been prohibited since 1974 when it was supplied as Laetrile or vitamin B17, a purported treatment for cancer with serious toxicity and no clear evidence of therapeutic benefit^[4],^[5]. I am concerned that the down-scheduling of amygdalin may contribute to excessive use of amygdalin, particularly where people who have or who have had cancer are seeking alternative treatments.

The applicant describes indications of amygdalin use as "cough and wheezing, profuse sputum, masses, lung abscess and intestinal abscess". I find these indications are likely to require medical diagnosis, management or monitoring by a trained medical practitioner. I note that a TCM practitioner does not have authority to prescribe Schedule 4 medicines, unless they are also registered as a medical practitioner. Having considered the findings of the external expert evaluation, which indicates there is less evidence for the safety of higher doses of amygdalin, I find that listing under Schedule 4 is not appropriate.

I have taken into consideration the two public submissions from the NSW Poisons Information Centre (NSW PIC) and the Australian Medical Association (AMA), whom both oppose this decision. The NSW PIC have documented 8 incidences over 6 years of amygdalin/cyanide poisoning resulting from intentional ingestion. There is serious concerns of the risks associated with deliberate self-poisonings and chronic overuse of these products.

I also do not support the down-scheduling of amygdalin at 5 mg or less to unscheduled, to align with the limits set by the Australian New Zealand Food Standards (FSANZ). The FSANZ food limits are based on the Acute Reference Dose (ARfD) for a safe level of one-off exposure, rather than regular and possibly chronic ingestion, which is the assumed practice for a TCM. The submission from the AMA raises similar concerns of serious risks associated with hydrocyanic acid accumulation in the body ^[6],^[7].

I note the conclusion of the external evaluation report, that exclusion from Schedule 10 for preparations containing a maximum daily dose not exceeding 5 mg amygdalin, may be appropriate. Notwithstanding the evidence that the risk of toxicity at this proposed cut-off may be low, I find there are factors which make it inappropriate for amygdalin to be available in a general sales environment. In particular, there is potential for use by children and use as an alternative cancer treatment. Fatalities have been recorded following doses of 0.5 to 2.5 grams of amygdalin, particularly in children. There is also significant inter-individual variability in the toxic response to amygdalin ingestion. For these reasons, I am of the view that such products cannot be supplied with reasonable safety with or without access to health professional advice.

The risks to public health and the toxicity of amygdalin associated hydrocyanic acid are evident^[8] and significantly outweigh the benefit of increased access.