Amygdalin
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Amygdalin (from Ancient Greek: {{#invoke:Lang|lang}} {{#invoke:Lang|lang}} 'almond') is a naturally occurring chemical compound found in many plants, most notably in the seeds (kernels, pips or stones) of apricots, bitter almonds, apples, peaches, cherries and plums, and in the roots of manioc.
Amygdalin is classified as a cyanogenic glycoside, because each amygdalin molecule includes a nitrile group, which can be released as the toxic cyanide anion by the action of a beta-glucosidase. Eating amygdalin will cause it to release cyanide in the human body, and may lead to cyanide poisoning.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Since the early 1950s, both amygdalin and a chemical derivative named laetrile have been promoted as alternative cancer treatments, often under the misnomer vitamin B17 (neither amygdalin nor laetrile is a vitamin).<ref name=CaCancer/> Scientific study has found them to not only be clinically ineffective in treating cancer, but also potentially toxic or lethal when taken by mouth due to cyanide poisoning.<ref name=Milazzo2015>Template:Cite journal</ref> The promotion of laetrile to treat cancer has been described in the medical literature as a canonical example of quackery<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> and as "the slickest, most sophisticated, and certainly the most remunerative cancer quack promotion in medical history".<ref name=CaCancer/> It has also been described as traditional Chinese medicine.<ref>Template:Cite journal</ref>
SourcesEdit
Amygdalin is contained in Rosaceae plants <ref>Template:Cite journal</ref> stone fruit kernels, such as almonds, apricot (14 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).<ref>Template:Cite journal</ref> 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.<ref name="LeeZhang2013">Template:Cite journal</ref>
ChemistryEdit
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.<ref>Template:Cite journal</ref>
Benzaldehyde released from amygdalin provides a bitter flavor. Because of a difference in a recessive gene called Sweet kernal [Sk], much less amygdalin is present in nonbitter (or sweet) almond than bitter almond.<ref name="Sanchez-PerezJorgensen2008">Template:Cite journal</ref>
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.<ref>Template:Cite EB1911</ref> 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.<ref>Template:Cite journal</ref>
Amygdalin is hydrolyzed by intestinal β-glucosidase (emulsin)<ref>Template:Cite book</ref> 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.<ref name="ATSDR 2014">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
LaetrileEdit
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 separate words "laevorotatory" and "mandelonitrile". Laevorotatory describes the stereochemistry of the molecule, while mandelonitrile refers to the portion of the molecule from which cyanide is released by decomposition.<ref name="NCIpdq">Template:Cite journal</ref> A 500 mg laetrile tablet may contain between 2.5 and 25 mg of hydrogen cyanide.<ref>Template:Cite book</ref>
Like amygdalin, laetrile is hydrolyzed in the duodenum (alkaline) and in 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.<ref>Template:Cite journal</ref>
Claims for laetrile were based on three different hypotheses:<ref name="Duke 2003">Template:Cite book</ref> The first hypothesis proposed that cancerous cells contained copious beta-glucosidases, which release HCN from laetrile via hydrolysis. Normal cells were reportedly unaffected, because they contained low concentrations of beta-glucosidases and high concentrations of rhodanese, which converts HCN to the less toxic thiocyanate. Later, however, it was shown that both cancerous and normal cells contain only trace amounts of beta-glucosidases and similar amounts of rhodanese.<ref name="Duke 2003" />
The second proposed that, after ingestion, amygdalin was hydrolyzed to mandelonitrile, transported intact to the liver and converted to a beta-glucuronide complex, which was then carried to the cancerous cells, hydrolyzed by beta-glucuronidases to release mandelonitrile and then HCN. Mandelonitrile, however, dissociates to benzaldehyde and hydrogen cyanide, and cannot be stabilized by glycosylation.<ref name="EFSA 2016">Template:Cite journal</ref>Template:Rp
Finally, the third asserted that laetrile is the discovered vitamin B-17, and further suggests that cancer is a result of "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.<ref name="pmid1154776">Template:Cite journal</ref> The term "vitamin B-17" is not recognized by Committee on Nomenclature of the American Institute of Nutrition Vitamins.<ref name="NCIpdq" /> 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.<ref name=CaCancer>Template:Cite journal</ref>
History of laetrileEdit
Early usageEdit
Amygdalin was first isolated in 1830 from bitter almond seeds (Prunus dulcis) by Pierre-Jean Robiquet and Antoine Boutron-Charlard.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Liebig and Wöhler found three hydrolysis products of amygdalin: sugar, benzaldehyde, and hydrogen cyanide.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>
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.<ref name=CancerInstitute/> In the 1950s, a purportedly non-toxic, synthetic form was patented for use as a meat preservative,<ref name=patent>Template:Cite patent</ref> and later marketed as laetrile for cancer treatment.<ref name=CancerInstitute/>
The U.S. Food and Drug Administration prohibited the interstate shipment of amygdalin and laetrile in 1977.<ref>Template:Cite book</ref><ref>Template:Cite journal</ref> Thereafter, 27 U.S. states legalized the use of amygdalin within those states.<ref>Template:Cite journal</ref>
Subsequent resultsEdit
In a 1977 controlled, blinded trial, laetrile showed no more activity than placebo.<ref name="Wade1977"/>
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."<ref name=Wade1977/> Mistakes in an earlier MSKCC press release were highlighted by a group of laetrile proponents led by Ralph Moss, former public affairs official of MSKCC who had been fired following his appearance at a press conference accusing the hospital of covering up the benefits of laetrile.<ref name="Budiansky1995">Template:Cite news</ref> These mistakes were considered scientifically inconsequential, but Nicholas Wade in Science stated that "even the appearance of a departure from strict objectivity is unfortunate."<ref name=Wade1977>Template:Cite journal</ref> The results from these studies were published all together.<ref>Template:Cite journal
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A 2015 systematic review from the Cochrane Collaboration found: <templatestyles src="Template:Blockquote/styles.css" />
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The authors also recommended, on ethical and scientific grounds, that no further clinical research into laetrile or amygdalin be conducted.<ref name=Milazzo2015 /> Subsequent research has confirmed the evidence of harm and lack of benefit.<ref>Template:Cite journal</ref>
Given the lack of evidence, laetrile has not been approved by the U.S. Food and Drug Administration or the European Commission.
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.<ref name =CancerInstitute>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> For example, a 1982 trial by the Mayo Clinic of 175 patients found that tumor size had increased in all but one patient.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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."<ref name =CancerInstitute />
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".<ref name="EFSA 2016" />
Advocacy and legality of laetrileEdit
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.<ref name=ConsumerReports/>
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.<ref name=ConsumerReports/>
Despite the lack of evidence for its use, laetrile developed a significant following due to its wide promotion as a "pain-free" treatment of cancer as an alternative to surgery and chemotherapy that have significant side effects. The use of laetrile led to a number of deaths.<ref name=ConsumerReports>Template:Cite book</ref> 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.<ref>Template:Cite journal</ref>
Some American cancer patients have traveled to Mexico for treatment with the substance, for example at the Oasis of Hope Hospital in Tijuana.<ref name=Moss2005>Template:Cite journal</ref> 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 D. 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, and a specific diet as well as laetrile.<ref>Template:Cite news</ref>
Laetrile advocates in the United States include Dean Burk, a former chief chemist of the National Cancer Institute cytochemistry laboratory,<ref>Template:Cite news</ref> 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.<ref>Template:Cite book</ref> The court also found that Vale had made at least $500,000 from his fraudulent sales of laetrile.<ref>Template:Cite news</ref>
In New Zealand, laetrile was among the purported treatments for cancer promoted by Milan Brych, who was later convicted of medical fraud.<ref>Template:Cite news</ref>
In the 1970s, court cases in several states challenged the FDA's authority to restrict access to what they claimed are 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<ref>Template:Cite court</ref> which established that interstate transport of the compound was illegal, usage fell off dramatically.<ref name="NCIpdq" /><ref name="Curran1980">Template:Cite journal</ref> The US Food and Drug Administration 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."<ref name=usfda>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>