Editing Amygdalin (section)

== Laetrile ==
{{Chembox
| Name = Laetrile
| ImageFile = Laetrile.svg
| ImageSize =
| ImageAlt =
| ImageClass = skin-invert-image
| IUPACName = (2''S'',3''S'',4''S'',5''R'',6''R'')-6-[(''R'')-cyano(phenyl)methoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid
| OtherNames = <small>L</small>-mandelonitrile-β-<small>D</small>-glucuronide, Vitamin B<sub>17</sub>
|Section1={{Chembox Identifiers
| CASNo = 1332-94-1
| PubChem = 5484354
|  ChemSpiderID = 4588479
|  SMILES = c1ccc(cc1)[C@H](C#N)O[C@H]2[C@@H]([C@H]([C@@H]([C@H](O2)C(=O)O)O)O)O
|  StdInChI = 1S/C14H15NO7/c15-6-8(7-4-2-1-3-5-7)21-14-11(18)9(16)10(17)12(22-14)13(19)20/h1-5,8-12,14,16-18H,(H,19,20)/t8-,9-,10-,11+,12-,14+/m0/s1
|  StdInChIKey = XLSLFPQAPYONPW-WHUHBCJBSA-N
}}
|Section2={{Chembox Properties
| Formula =
| C=14 | H=15 | N=1 | O=7
| MolarMass = 309.2714
| Appearance =
| Density =
| MeltingPtC = 214 to 216
| BoilingPt =
| Solubility =
}}
|Section3={{Chembox Hazards
| MainHazards =
| FlashPt =
| AutoignitionPt =
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}}

Laetrile (patented 1961) is a simpler semisynthetic [[Derivative (chemistry)|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">{{cite journal |title=Laetrile/Amygdalin (PDQ)–Health Professional Version: General Information |date=15 March 2017 |pmid=26389425 |url=https://www.cancer.gov/about-cancer/treatment/cam/hp/laetrile-pdq#section/_5 |website=Cancer.gov |publisher=National Cancer Institute |series=Complementary and Alternative Medicine for Health Professionals |access-date=9 May 2017 |author1=PDQ Integrative, Alternative, and Complementary Therapies Editorial Board }}</ref> A 500&nbsp;mg laetrile tablet may contain between 2.5 and 25&nbsp;mg of hydrogen cyanide.<ref>{{cite book |veditors=Leikin JB, Paloucek FP |chapter=Laetrile |title=Poisoning and Toxicology Handbook |edition=4th |publisher=Informa |date=2008 |page=950 |isbn=978-1-4200-4479-9 }}</ref>

Like amygdalin, laetrile is hydrolyzed in the duodenum (alkaline) and in the intestine (enzymatically) to <small>D</small>-[[glucuronic acid]] and <small>L</small>-[[mandelonitrile]]; the latter hydrolyzes to benzaldehyde and hydrogen cyanide, that in sufficient quantities causes [[cyanide poisoning]].<ref>{{cite journal | vauthors = Rietjens IM, Martena MJ, Boersma MG, Spiegelenberg W, Alink GM | title = Molecular mechanisms of toxicity of important food-borne phytotoxins | journal = Molecular Nutrition & Food Research | volume = 49 | issue = 2 | pages = 131–158 | date = February 2005 | pmid = 15635687 | doi = 10.1002/mnfr.200400078 }}</ref>

Claims for laetrile were based on three different hypotheses:<ref name="Duke 2003">{{cite book |vauthors=Duke JA |title=CRC Handbook of Medicinal Spices |publisher=CRC Press |date=2003 |isbn=978-0-8493-1279-3 |pages=261–262 }}</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">{{cite journal |author=EFSA Panel on Contaminants in the Food Chain (CONTAM) |title=Acute Health Risks Related to the Presence of Cyanogenic Glycosides in Raw Apricot Kernels and Products Derived from Raw Apricot Kernels |journal=EFSA Journal |volume=14 |issue=4 |date=2016 |doi=10.2903/j.efsa.2016.4424 |doi-access=free |hdl=2164/7789 |hdl-access=free }}</ref>{{Rp|9}}

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">{{cite journal | vauthors = Greenberg DM | title = The vitamin fraud in cancer quackery | journal = The Western Journal of Medicine | volume = 122 | issue = 4 | pages = 345–348 | date = April 1975 | pmid = 1154776 | pmc = 1129741 }}</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>{{cite journal | vauthors = Lerner IJ | title = Laetrile: a lesson in cancer quackery | journal = CA: A Cancer Journal for Clinicians | volume = 31 | issue = 2 | pages = 91–95 |date= 1981 | pmid = 6781723 | doi = 10.3322/canjclin.31.2.91 | s2cid = 28917628 | doi-access = free }}</ref>

=== History of laetrile ===

==== Early usage ====
Amygdalin was first isolated in 1830 from [[bitter almond]] seeds (''[[Prunus dulcis]]'') by [[Pierre-Jean Robiquet]] and [[Antoine François Boutron Charlard|Antoine Boutron-Charlard]].<ref>{{cite web | vauthors = von Sengbusch P |title=A chronology of significant historical developments in the biological sciences |work=Botany Online Internet Hypertextbook |publisher=[[University of Hamburg]], Department of Biology |date=18 August 2002 |url=http://www.biologie.uni-hamburg.de/b-online/e01/geschichte.htm |access-date=6 August 2007 |archive-url=https://web.archive.org/web/20070820063617/http://www.biologie.uni-hamburg.de/b-online/e01/geschichte.htm |archive-date=20 August 2007 |url-status=dead }}</ref> [[Justus von Liebig|Liebig]] and [[Friedrich Woehler|Wöhler]] found three [[hydrolysis]] products of amygdalin: sugar, benzaldehyde, and [[hydrogen cyanide]].<ref>{{cite journal | title=Ueber die Bildung des Bittermandelöls | vauthors = Wöhler F, Liebig J | journal=Annalen der Pharmacie | year=1837 | volume=22 | issue=1 | pages=1–24 | doi=10.1002/jlac.18370220102|s2cid=96869201 |url=https://zenodo.org/record/1426920 }}</ref> Later research showed that [[sulfuric acid]] hydrolyzes it into [[D-glucose|<small>D</small>-glucose]], benzaldehyde, and hydrogen cyanide; while [[hydrochloric acid]] gives [[mandelic acid]], <small>D</small>-glucose, and [[ammonia]].<ref>{{cite journal | title=The hydrolysis of amygdalin by acids. Part I | vauthors = Walker JW, Krieble VK | journal=[[Journal of the Chemical Society]] | year=1909 | volume=95 | issue=11 | pages=1369–77 | doi=10.1039/CT9099501369}}</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>{{Cite patent| inventor = Krebs Jr ET | pubdate = 23 May 1961 | title = Hexuronic acid derivatives | url = http://www.freepatentsonline.com/2985664.html | country = US | number = 2985664 | gdate = 23 May 1961 }}</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>{{cite book| vauthors = Carpenter D |title= Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA. Princeton: Princeton University Press.|year=2010|publisher=Princeton University Press|location=Princeton|isbn=978-0-691-14180-0}}</ref><ref>{{cite journal | vauthors = Kennedy D |date= 1977 | url = http://www.cancertreatmentwatch.org/q/laetrile/commissioner.pdf | title = Laetrile: The Commissioner's Decision | journal = [[Federal Register]] | volume = Docket No. 77-22310}}</ref> Thereafter, 27 U.S. states legalized the use of amygdalin within those states.<ref>{{cite journal | vauthors = <!-- Not listed --> | title = Unproven methods of cancer management. Laetrile | journal = CA: A Cancer Journal for Clinicians | publisher = American Cancer Society | volume = 41 | issue = 3 | pages = 187–192 |date= 1991 | pmid = 1902140 | doi = 10.3322/canjclin.41.3.187 | s2cid = 5932239 | doi-access = free }}</ref>

==== Subsequent results ====
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&ndash;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 W. Moss (science writer)|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">{{cite news| vauthors = Budiansky S |title=Cures or Quackery: How Senator Harkin shaped federal research on alternative medicine |date=9 July 1995 |url=https://www.usnews.com/usnews/culture/articles/950717/archive_032434.htm |work=U.S. News & World Report |access-date=7 November 2009 |url-status=dead |archive-url=https://web.archive.org/web/20110903141336/http://www.usnews.com/usnews/culture/articles/950717/archive_032434.htm |archive-date=3 September 2011 }}</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>{{cite journal | vauthors = Wade N | title = Laetrile at sloan-kettering: a question of ambiguity | journal = Science | volume = 198 | issue = 4323 | pages = 1231–1234 | date = December 1977 | pmid = 17741690 | doi = 10.1126/science.198.4323.1231 | bibcode = 1977Sci...198.1231W }}</ref> The results from these studies were published all together.<ref>{{cite journal | vauthors = Stock CC, Tarnowski GS, Schmid FA, Hutchison DJ, Teller MN | title = Antitumor tests of amygdalin in transplantable animal tumor systems | journal = Journal of Surgical Oncology | volume = 10 | issue = 2 | pages = 81–88 |date= 1978 | pmid = 642516 | doi = 10.1002/jso.2930100202 | s2cid = 5896930 }}<br />
{{cite journal | vauthors = Stock CC, Martin DS, Sugiura K, Fugmann RA, Mountain IM, Stockert E, Schmid FA, Tarnowski GS | title = Antitumor tests of amygdalin in spontaneous animal tumor systems | journal = Journal of Surgical Oncology | volume = 10 | issue = 2 | pages = 89–123 |date= 1978 | pmid = 347176 | doi = 10.1002/jso.2930100203 | s2cid = 22185766 }}</ref>

A 2015 [[systematic review]] from the [[Cochrane Collaboration]] found: {{blockquote|<nowiki>The claims that laetrile or amygdalin have beneficial effects for cancer patients are not currently supported by sound clinical data. There is a considerable risk of serious adverse effects from cyanide poisoning after laetrile or amygdalin, especially after oral ingestion. The risk–benefit balance of laetrile or amygdalin as a treatment for cancer is therefore unambiguously negative.</nowiki><ref name=Milazzo2015 />|sign=|source=}}

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>{{cite journal | vauthors = He XY, Wu LJ, Wang WX, Xie PJ, Chen YH, Wang F | title = Amygdalin – A pharmacological and toxicological review | journal = Journal of Ethnopharmacology | volume = 254 | pages = 112717 | date = May 2020 | pmid = 32114166 | doi = 10.1016/j.jep.2020.112717 }}</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>{{cite web|url=http://www.cancer.gov/cancertopics/pdq/cam/laetrile/patient/allpages#Section_20|title=Laetrile/Amygdalin|publisher=National Cancer Institute|date=23 September 2005}}</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>{{cite web |url=http://www.cancerhelp.org.uk/about-cancer/treatment/complementary-alternative/therapies/laetrile |title=Laetrile (amygdalin, vitamin B17) |website=CancerHelp.org.uk |date=30 August 2017 }}</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 laetrile ===
Advocates for laetrile assert that there is a [[conspiracy theory|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>{{Cite book | title = Health Quackery | place = Vernon, New York | publisher = Consumers Union |date= 1980 | chapter = Laetrile: the Political Success of a Scientific Failure | pages = [https://archive.org/details/healthquackeryco00cons/page/16 16–40] | isbn = 978-0-89043-014-9 | chapter-url-access = registration | chapter-url = https://archive.org/details/healthquackeryco00cons | url = https://archive.org/details/healthquackeryco00cons/page/16 }}</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>{{cite journal | vauthors = Herbert V | title = Laetrile: the cult of cyanide. Promoting poison for profit | journal = The American Journal of Clinical Nutrition | volume = 32 | issue = 5 | pages = 1121–1158 | date = May 1979 | pmid = 219680 | doi = 10.1093/ajcn/32.5.1121 | doi-access = free }}</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>{{cite journal | vauthors = Moss RW | title = Patient perspectives: Tijuana cancer clinics in the post-NAFTA era | journal = Integrative Cancer Therapies | volume = 4 | issue = 1 | pages = 65–86 | date = March 2005 | pmid = 15695477 | doi = 10.1177/1534735404273918 | doi-access = free }}</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 Donald Kelley|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>{{cite news|url=https://www.nytimes.com/2005/11/15/health/15essa.html?ex=1289710800&en=8059981c17deec5d&ei=5088|title=McQueen's Legacy of Laetrile|newspaper=The New York Times|date=15 November 2005 | vauthors = Lerner BH | access-date=23 April 2010}}</ref>

Laetrile advocates in the United States include [[Dean Burk]], a former chief chemist of the [[National Cancer Institute]] [[cytochemistry]] laboratory,<ref>{{cite news | vauthors = Whitaker JD | url = http://www.highbeam.com/doc/1P2-1283487.html | title = Dean Burk, 84, Noted Chemist at National Cancer Institute, Dies | newspaper = The Washington Post| date = 9 October 1988 | access-date = 14 January 2007 | archive-url = https://web.archive.org/web/20121105073833/http://www.highbeam.com/doc/1P2-1283487.html | archive-date = 5 November 2012 | url-status = dead }}</ref> and national [[arm wrestling]] champion Jason Vale, who falsely claimed that his [[kidney cancer|kidney]] and [[pancreatic cancer|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>{{cite book | vauthors = McWilliams BS |title=Spam kings: the real story behind the high-rolling hucksters pushing porn, pills and @*#?% enlargements |publisher=O'Reilly |location=Sebastopol, CA |year=2005 |isbn=978-0-596-00732-4 |url=https://archive.org/details/spamkingsrealsto00mcwi| url-access = registration | page = [https://archive.org/details/spamkingsrealsto00mcwi/page/237 237] | quote = Jason Vale. }}</ref> The court also found that Vale had made at least $500,000 from his fraudulent sales of laetrile.<ref>{{cite news |url=http://www.medicalnewstoday.com/articles/9825.php | archive-url = https://web.archive.org/web/20101204113541/http://www.medicalnewstoday.com/articles/9825.php | archive-date = 4 December 2010 |title=New York Man Sentenced to 63 Months for Selling Fake Cancer Cure |date=22 June 2004 |work=Medical News Today |access-date=8 July 2010}}</ref>

In New Zealand, laetrile was among the purported treatments for cancer promoted by [[Milan Brych]], who was later convicted of medical fraud.<ref>{{Cite news|url=https://www.stuff.co.nz/national/130651208/alternative-cancer-treatments--helpful-or-harmful|title=Alternative cancer treatments – helpful or harmful?|first=Nadine|last=Roberts|publisher=Stuff|date=3 December 2022|access-date=3 November 2024}}</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>{{cite court |litigants= United States v. Rutherford |vol= 442 |reporter= U.S. |opinion= 544 |court= United States Supreme Court |date= 1979 |url= http://caselaw.lp.findlaw.com/scripts/getcase.pl?navby=CASE&court=US&vol=442&page=544 }}</ref> which established that interstate transport of the compound was illegal, usage fell off dramatically.<ref name="NCIpdq" /><ref name="Curran1980">{{cite journal | vauthors = Curran WJ | title = Law-medicine notes. Laetrile for the terminally ill: Supreme Court stops the nonsense | journal = The New England Journal of Medicine | volume = 302 | issue = 11 | pages = 619–621 | date = March 1980 | pmid = 7351911 | doi = 10.1056/NEJM198003133021108 }}</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>{{cite web |publisher= FDA |date= 22 June 2004 |url= https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2004/ucm108314.htm |title= Lengthy Jail Sentence for Vendor of Laetrile – A Quack Medication to Treat Cancer Patients |archive-url= https://web.archive.org/web/20090710102512/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2004/ucm108314.htm |archive-date= 10 July 2009 }}</ref>