Amygdalin

Sources

Amygdalin is contained in Rosaceae plants, stone fruit kernels, such as almonds, apricot (14 g/kg), red cherry (3.9 g/kg), black cherry (2.7 g/kg), peach (6.8 g/kg), and plum (4–17.5 g/kg depending on variety), and also in the seeds of the apple (3 g/kg). In one study, bitter almond amygdalin concentrations ranged from 33 to 54 g/kg depending on variety; semibitter varieties averaged 1 g/kg and sweet varieties averaged 0.063 g/kg with significant variability based on variety and growing region.

Chemistry

Amygdalin is a cyanogenic glycoside derived from the aromatic amino acid phenylalanine. Amygdalin and prunasin are common among plants of the family Rosaceae, particularly the genus Prunus, Poaceae (grasses), Fabaceae (legumes), and in other food plants, including flaxseed and manioc. Within these plants, amygdalin and the enzymes necessary to hydrolyze it are stored in separate locations, and only mix as a result of tissue damage. This provides a natural defense system.

Benzaldehyde released from amygdalin provides a bitter flavor. Because of a difference in a recessive gene called Sweet kernel [Sk], much less amygdalin is present in nonbitter (or sweet) almond than bitter almond.

For one method of isolating amygdalin, the stones are removed from the fruit and cracked to obtain the kernels, which are dried in the sun or in ovens. The kernels are boiled in ethanol; on evaporation of the solution and the addition of diethyl ether, amygdalin is precipitated as minute white crystals. Natural amygdalin has the (R)-configuration at the chiral phenyl center. Under mild basic conditions, this stereogenic center isomerizes; the (S)-epimer is called neoamygdalin. Although the synthesized version of amygdalin is the (R)-epimer, the stereogenic center attached to the nitrile and phenyl groups easily epimerizes if the manufacturer does not store the compound correctly.

Amygdalin is hydrolyzed by intestinal β-glucosidase (emulsin) and amygdalin beta-glucosidase (amygdalase) to give gentiobiose and L-mandelonitrile. Gentiobiose is further hydrolyzed to give glucose, whereas mandelonitrile (the cyanohydrin of benzaldehyde) decomposes to give benzaldehyde and hydrogen cyanide. Hydrogen cyanide in sufficient quantities (allowable daily intake: ~0.6 mg) causes cyanide poisoning which has a fatal oral dose range of 0.6–1.5 mg/kg of body weight.

Laetrile

Laetrile (patented 1961) is a simpler semisynthetic derivative of amygdalin. Laetrile is synthesized from amygdalin by hydrolysis. The usual preferred commercial source is from apricot kernels (Prunus armeniaca). The name is derived from the words "laevorotatory" (referring to the molecule's stereochemistry) and "mandelonitrile" (the portion of the molecule from which cyanide is released by decomposition). A 500 mg laetrile tablet may contain between 2.5 and 25 mg of hydrogen cyanide.

Like amygdalin, laetrile is hydrolyzed in the duodenum (alkaline) and the intestine (enzymatically) to D-glucuronic acid and L-mandelonitrile; the latter hydrolyzes to benzaldehyde and hydrogen cyanide, that in sufficient quantities causes cyanide poisoning.

Claims for laetrile were based on three different hypotheses. One claimed that amygdalin was hydrolyzed to mandelonitrile, converted to a beta-glucuronide complex in the liver, then carried to cancer cells where it would release mandelonitrile and HCN. Mandelonitrile, however, dissociates to benzaldehyde and hydrogen cyanide, and cannot be stabilized by glycosylation.

Finally, the third asserted that laetrile is the discovered vitamin B-17, further suggesting that cancer results from "B-17 deficiency". It postulated that regular dietary administration of this form of laetrile would, therefore, actually prevent all incidences of cancer. There is no evidence supporting this conjecture in the form of a physiologic process, nutritional requirement, or identification of any deficiency syndrome. The term "vitamin B-17" is not recognized by Committee on Nomenclature of the American Institute of Nutrition Vitamins. Ernst T. Krebs (not to be confused with Hans Adolf Krebs, the discoverer of the citric acid cycle) branded laetrile as a vitamin in order to have it classified as a nutritional supplement rather than as a pharmaceutical.

History of laetrile

Early usage

Amygdalin was first isolated in 1830 from bitter almond seeds (Prunus dulcis) by Pierre-Jean Robiquet and Antoine Boutron-Charlard. Justus von Liebig and Friedrich Woehler found three hydrolysis products of amygdalin: sugar, benzaldehyde, and hydrogen cyanide. Later research showed that sulfuric acid hydrolyzes it into D-glucose, benzaldehyde, and hydrogen cyanide; while hydrochloric acid gives mandelic acid, D-glucose, and ammonia.

In 1845, amygdalin was used as a cancer treatment in Russia, and in the 1920s in the United States, but it was considered too poisonous. and later marketed as laetrile for cancer treatment.

The U.S. Food and Drug Administration prohibited the interstate shipment of amygdalin and laetrile in 1977. Thereafter, 27 U.S. states legalized the use of amygdalin within those states.

Subsequent results

In a 1977 controlled, blinded trial, laetrile showed no more activity than placebo. Subsequently, laetrile was tested on 14 tumor systems without evidence of effectiveness. The Memorial Sloan–Kettering Cancer Center (MSKCC) concluded that "laetrile showed no beneficial effects." These mistakes were considered scientifically inconsequential, but Nicholas Wade, in Science, stated that "even the appearance of a departure from strict objectivity is unfortunate." The results from these studies were published all together.

A 2015 systematic review from the Cochrane Collaboration found:

The authors also recommended, on ethical and scientific grounds, that no further clinical research into laetrile or amygdalin be conducted.

Given the lack of evidence, neither the U.S. Food and Drug Administration nor the European Commission has approved laetrile. The U.S. National Institutes of Health evaluated the evidence separately and concluded that clinical trials of amygdalin showed little or no effect against cancer. For example, a 1982 trial by the Mayo Clinic of 175 patients found that tumor size had increased in all but one patient. The authors reported that "the hazards of amygdalin therapy were evidenced in several patients by symptoms of cyanide toxicity or by blood cyanide levels approaching the lethal range." The study concluded, "Patients exposed to this agent should be instructed about the danger of cyanide poisoning, and their blood cyanide levels should be carefully monitored. Amygdalin (Laetrile) is a toxic drug that is not effective as a cancer treatment".

Additionally, "No controlled clinical trials (trials that compare groups of patients who receive the new treatment to groups who do not) of laetrile have been reported."

The side effects of laetrile treatment are the symptoms of cyanide poisoning. These symptoms include: nausea and vomiting, headache, dizziness, cherry red skin color, liver damage, abnormally low blood pressure, droopy upper eyelid, trouble walking due to damaged nerves, fever, mental confusion, coma, and death.

The European Food Safety Agency's Panel on Contaminants in the Food Chain has studied the potential toxicity of the amygdalin in apricot kernels. The Panel reported, "If consumers follow the recommendations of websites that promote consumption of apricot kernels, their exposure to cyanide will greatly exceed" the dose expected to be toxic. The Panel also reported that acute cyanide toxicity had occurred in adults who had consumed 20 or more kernels and that in children, "five or more kernels appear to be toxic".

Advocacy and legality of laetrile

Advocates for laetrile assert that there is a conspiracy between the US Food and Drug Administration, the pharmaceutical industry, and the medical community, including the American Medical Association and the American Cancer Society, to exploit the American people, and especially cancer patients.

Advocates of the use of laetrile have also changed the rationale for its use, first as a treatment of cancer, then as a vitamin, then as part of a "holistic" nutritional regimen, or as treatment for cancer pain, among others, none of which have any significant evidence supporting its use. The FDA and AMA crackdown, begun in the 1970s, effectively escalated prices on the black market, played into the conspiracy narrative, and enabled unscrupulous profiteers to foster multimillion-dollar smuggling empires.

Some American cancer patients have traveled to Mexico for treatment with the substance, for example at the Oasis of Hope Hospital in Tijuana. The actor Steve McQueen died in Mexico following surgery to remove a stomach tumor, having previously undergone extended treatment for pleural mesothelioma—a cancer associated with asbestos exposure—under the care of William Donald Kelley, a de-licensed dentist and orthodontist who claimed to have devised a cancer treatment involving pancreatic enzymes, 50 daily vitamins and minerals, frequent body shampoos, enemas, a specific diet, and laetrile.

Laetrile advocates in the United States include Dean Burk, a former chief chemist of the National Cancer Institute cytochemistry laboratory, and national arm wrestling champion Jason Vale, who falsely claimed that his kidney and pancreatic cancers were cured by eating apricot seeds. Vale was convicted in 2004 for, among other things, fraudulently marketing laetrile as a cancer cure. The court also found that Vale had made at least $500,000 from his fraudulent sales of laetrile.

In New Zealand, laetrile was among the purported treatments for cancer promoted by Milan Brych, who was later convicted of medical fraud.

In the 1970s, court cases in several states challenged the FDA's authority to restrict access to what they claimed were potentially lifesaving drugs. More than twenty states passed laws making the use of laetrile legal. After the unanimous Supreme Court ruling in United States v. Rutherford, which established that interstate transport of the compound was illegal, usage fell off dramatically. The FDA continues to seek jail sentences for vendors marketing laetrile for cancer treatment, calling it a "highly toxic product that has not shown any effect on treating cancer."

References

References

1. (27 April 2016). "Apricot kernels pose risk of cyanide poisoning". European Food Safety Authority.
2. (April 2015). "Laetrile Treatment for Cancer". The Cochrane Database of Systematic Reviews.
3. (February 1984). "The Whys of Cancer Quackery". Cancer.
4. (1984). "Laetrile: The Regulatory Challenge of an Unproven Remedy". Public Health Reports.
5. (2012). "Amygdalin content in four stone fruit species at different developmental stages". [[ScienceAsia]].
6. (2014). "Amygdalin content of seeds, kernels and food products commercially-available in the UK". Food Chemistry.
7. (August 2013). "Quantification of amygdalin in nonbitter, semibitter, and bitter almonds (Prunus dulcis) by UHPLC-(ESI)QqQ MS/MS". Journal of Agricultural and Food Chemistry.
8. (May 2016). "Application of the Prunus spp. Cyanide Seed Defense System onto Wheat: Reduced Insect Feeding and Field Growth Tests". Journal of Agricultural and Food Chemistry.
9. (March 2008). "Bitterness in almonds". Plant Physiology.
10. {{Cite EB1911
11. (October 2015). "Problems and Pitfalls in the Analysis of Amygdalin and Its Epimer". Journal of Agricultural and Food Chemistry.
12. (1975). "Practical Organic Chemistry". Longman.
13. (21 October 2014). "Medical Management Guidelines (MMGs): Hydrogen Cyanide (HCN)".
14. (15 March 2017). "Laetrile/Amygdalin (PDQ)–Health Professional Version: General Information". National Cancer Institute.
15. (2008). "Poisoning and Toxicology Handbook". Informa.
16. (February 2005). "Molecular mechanisms of toxicity of important food-borne phytotoxins". Molecular Nutrition & Food Research.
17. (2003). "CRC Handbook of Medicinal Spices". CRC Press.
18. EFSA Panel on Contaminants in the Food Chain (CONTAM). (2016). "Acute Health Risks Related to the Presence of Cyanogenic Glycosides in Raw Apricot Kernels and Products Derived from Raw Apricot Kernels". EFSA Journal.
19. (April 1975). "The vitamin fraud in cancer quackery". The Western Journal of Medicine.
20. (1981). "Laetrile: a lesson in cancer quackery". CA: A Cancer Journal for Clinicians.
21. (18 August 2002). "A chronology of significant historical developments in the biological sciences". [[University of Hamburg]], Department of Biology.
22. (1837). "Ueber die Bildung des Bittermandelöls". Annalen der Pharmacie.
23. (1909). "The hydrolysis of amygdalin by acids. Part I". [[Journal of the Chemical Society]].
24. "Hexuronic acid derivatives".
25. (2010). "Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA. Princeton: Princeton University Press.". Princeton University Press.
26. (1977). "Laetrile: The Commissioner's Decision". [[Federal Register]].
27. (1991). "Unproven methods of cancer management. Laetrile". American Cancer Society.
28. (9 July 1995). "Cures or Quackery: How Senator Harkin shaped federal research on alternative medicine". U.S. News & World Report.
29. (December 1977). "Laetrile at sloan-kettering: a question of ambiguity". Science.
30. (May 2020). "Amygdalin – A pharmacological and toxicological review". Journal of Ethnopharmacology.
31. (23 September 2005). "Laetrile/Amygdalin". National Cancer Institute.
32. (30 August 2017). "Laetrile (amygdalin, vitamin B17)".
33. (1980). "Health Quackery". Consumers Union.
34. (May 1979). "Laetrile: the cult of cyanide. Promoting poison for profit". The American Journal of Clinical Nutrition.
35. (March 2005). "Patient perspectives: Tijuana cancer clinics in the post-NAFTA era". Integrative Cancer Therapies.
36. (15 November 2005). "McQueen's Legacy of Laetrile". The New York Times.
37. (9 October 1988). "Dean Burk, 84, Noted Chemist at National Cancer Institute, Dies". The Washington Post.
38. (2005). "Spam kings: the real story behind the high-rolling hucksters pushing porn, pills and @*#?% enlargements". O'Reilly.
39. (22 June 2004). "New York Man Sentenced to 63 Months for Selling Fake Cancer Cure". Medical News Today.
40. Roberts, Nadine. (3 December 2022). "Alternative cancer treatments – helpful or harmful?". Stuff.
41. {{cite court. (1979). link
42. (March 1980). "Law-medicine notes. Laetrile for the terminally ill: Supreme Court stops the nonsense". The New England Journal of Medicine.
43. (22 June 2004). "Lengthy Jail Sentence for Vendor of Laetrile – A Quack Medication to Treat Cancer Patients". FDA.