The Current Status of Laetrile ROBERT T. DORR, M.S., R.Ph.; and JAMES PAXINOS,

Amygdalin at various concentrations and with numerous impurities is the most common cyanogenic glycoside found in laetrile samples. Its chemical properties were first described in 1837, and pharmacologic studies have shown that ultimately it is broken down to HCN, benzaldehyde, and glucose by enzymes found in gut bacteria but not intracellular^ in humans. Fatal and nonfatal toxicities to orally ingested cyanogenic glycosides have been reported worldwide. We review here the signs and symptoms of acute cyanide toxicity and its treatment. Substantial in-vitro and invivo testing in animal tumor systems has shown that amygdalin is entirely devoid of significant anticancer activity. Control animals often have lived longer than those treated with various doses and schedules of amygdalin. Acceptable clinical studies in humans are lacking, but such ventures would appear to be contraindicated from animal studies and observed human toxicities. We also discuss current legaljudicial aspects of laetrile therapy for cancer.


N E W DIMENSION IN MEDICINE has been introduced

with the recent "legalization** of laetrile in several states. Through a well-organized effort, popular support has been created for laetrile in the political arena. The success of the laetrile movement has occurred despite a total lack of any objective data documenting the slightest therapeutic value in cancer treatment. Testimony by leading experts in cancer treatment and research and the F D A have done little to impede the success that the laetrile supporters have achieved. Those who believe laetrile therapy is worthless and replete with "quackery" must now accept the fact that it has gained a great measure of respectability by the general public as a result of its recent legislative endorsement. We review here laetrile's effects from a scientific basis and its current legal and social status and project what can be expected because of recent legislative activities. This information hopefully will assist the health practitioner to deal with the laetrile controversy in the best interests of the patient. Chemistry

The term "laetrile" denotes a class of cyanogenic glucosides more correctly than it describes a single chemical • From the Department of Pharmacy and Supply, University of Arizona Health Sciences Center; Tucson, Arizona.

Annals of Internal Medicine 89:389- 397 , 1978

R.Ph.; Tucson, Arizona

entity. The nomenclature used by various authors has been conflicting. Most of the laetrile samples analyzed have actually been composed primarily of amygdalin with some impurities (1-3). Originally, the term laetrile was coined by E.T. Krebs, Jr., in the late 1940s as an acronym to describe a purified derivative of amygdalin *7aevo rotatory" in polarized light that was chemically a mandelonitn/e. Often laetrile is described as D-mandelonitrile-/3-glucoside (see Figure 1) (4). This substance is currently known as prunasin (5). Amygdalin, however, is the principal laetrile constituent and is a naturally occurring cyanoglucoside. It can be obtained from various plant sources (vetches, clovers, sorghums, cassava, lima beans, acacia) and, most notably, the pits of edible fruits and berries (apricots, peaches, plums, chokeberries) (5, 6). Chemically amygdalin is Dmandelonitrile-/3-D-glucoside-6-/3-D-glucoside (Figure 1). Many sources incorrectly use the two terms laetrile and amygdalin interchangeably. The chemical properties of amygdalin were first described by the German chemists Liebig and Wohler (7) in 1837 after having been isolated 7 years earlier by the French chemists Robiquet and Boutron (8). The synthesis of amygdalin was first reported in 1924 (9). The glycone portion of the molecule consists of two sugars, gentiobiose and 2-D-glucose, attached glycosidically to the genin or aglycone, D-mandelonitrile. This can be further broken down to benzaldehyde and hydrocyanic acid (HCN). The /3-glycosidic linkage can be hydrolized specifically by emulsin (found in almonds) and (5glucosidase. The compound contains several asymmetric carbons and therefore has optical activity in both the glycone and aglycone moieties. Hydrolysis of amygdalin by amgydalase, present in emulsin, yields the secondary glycoside prunasin and glucose (9). Prunasin can be further reduced by prunase to yield HCN, glucose, and benzaldehyde (10). In 1935 Vierhover and Mack (6) summarized the additional biochemical properties of amygdalin. They found that during in-vitro hydrolysis with emulsin and dilute acid, one molecule of HCN and benzaldehyde and two molecules of glucose were released. They also noted during toxicologic tests in dogs and rabbits with Daphnia (a translucent mollusk) that the rate of release of HCN was dependent on the concentration of the enzyme group, collectively termed emulsin. This rate directly correlated with the onset of cyanide symptoms and death in experimental animals. This same hydrolytic pattern occurred ©1978 American College of Physicians

Downloaded From: by a University of California San Diego User on 03/19/2017



Laetrile is produced by an extraction of ground apricot pits. Ironically, most laetrile produced in Mexico is obtained from fruit pits imported from California fruitpacking concerns. The extraction process involves defatting the ground pits, using ether or alcohol as solvents. It is estimated that 33 kernels are needed for each 500-mg tablet and 200 kernels for 3 g of the injectable (12). The tablets have sold from 65^ to $1, the injection from $6 to $9 per 3-g ampule (12). Pharmacology

Figure 1 . Chemical structures of the compounds commonly referred to as laetriles.

more slowly through digestive enzyme activity alone in higher animals. The benzaldehyde formed was a weak anesthetic agent (6). It is known now that benzaldehyde is rapidly oxidized in vivo to benzoic acid, which is not pharmacologically active. Thus the two common "laetriles" are amygdalin and prunasin, which contains one less glucose molecule. In vivo, the laetriles can only be cleaved specifically by the enzyme /3-glucosidase to yield glucose and mandelonitrile, the cyanohydrin of benzaldehyde. Further spontaneous breakdown of mandelonitrile would yield benzaldehyde and hydrocyanic acid (5). Chemical analysis of laetrile samples in a Canadian study in 1965 (1) found amygdalin concentrations of 8 7 % to 9 8 % with varying amounts of sucrose, phenol, and di-isopropyl ammonium iodide (a residue from the extraction process) (1). The methods used in that study included optical rotation, pH, appearance, spectral, and chemical analysis. More recently, injectable products from Mexican laboratories have shown significant amounts of unknown pyrogens as well as varying concentrations of both dextroand levo-amygdalin, whereas oral tablets similarly obtained have been primarily dextro-rotatory products (3). In fact, the actual amygdalin content of samples analyzed by the F D A , Stanford Research Laboratories, and others has varied from 42 to 450 mg (per 500 mg tablet) and from 14% to 8 7 % in injectable concentrations (3 g/10 ml). Some of the vials analyzed had visually apparent clouding due to microbial growth and some had defective seals, along with the presence of various amounts of extractant impurities such as isopropyl alcohol (11). 390

Since there has never been a well-controlled study of laetriles in humans, much of the pharmacology and kinetics must be derived from animal studies and anecdotal observations. The proposed anticancer mechanism of laetrile has changed several times over the years. The oldest and most familiar scheme purports that laetriles are "activated" in vivo by the enzyme /3-glucosidase, supposedly in high concentrations in cancer cells, to yield the hydrolytic products glucose and mandelonitrile. These in turn are cleaved either spontaneously or by a secondary enzyme to yield free hydrocyanic acid and benzaldehyde (see Figure 2). In this scheme normal cells and cancer cells must differ in the concentration of rhodanese (thiosulfurtransferase). This enzyme protects normal cells by converting H C N to the nontoxic thiocyanate form while allowing tumor cells, purportedly low in rhodanese, to be lethally affected by the H C N . This theory has been highly criticized. First, when administered parenterally, essentially all of the dose will probably be excreted intact in the urine (5). This follows from the fact that animal and human tissues contain only insignificant concentrations of /3-glucosidase, the only known activating enzyme of laetriles found in vivo (13). As a result, metabolic breakdown of the compound probably does not occur. Second, there is no differential distribution of the detoxifying enzyme rhodanese between normal and cancerous cells (14). This leaves a pharmacologic model that does not allow drug activation and provides nonselective

Figure 2. Purported mechanism of action of amygdalin or laetrile.

September 1978 • Annals of Internal Medicine • Volume 89 • Number 3

Downloaded From: by a University of California San Diego User on 03/19/2017

target toxicity and detoxification if it could become activated. When reports by Fishman and Anlyan (15, 16) showed relatively high concentrations of the enzyme glucuronidase in tumor cells, the theory shifted to involve liver conjugation of the mandelonitrile, supposedly formed after oral ingestion and hydrolysis of a laetrile. This mandelonitrile-glucuronide conjugate was then purportedly transported to cells where the glucuronidase concentration differential facilitated selective liberation of HCN by tumor cells. This proposed enzyme concentration differential, however, is not significant. Further, liver conjugation of mandelonitrile, if released in vivo at all, has never been demonstrated. A central argument to the entire question is whether cyanide can selectively kill cancer cells. An in-vitro Canadian study (1) using three primary human tumors and two animal ascites tumors confirmed earlier reports (17, 18) that cytotoxicity only occurred when cells were placed in a state of total glucose deprivation. If any glucose was present, the cells were able to resist the lethal effects of 0.1-nM concentrations of HCN applied directly to the culture medium. An in-vivo study by Brown, Wood, and Smith (19) of uterine cancer found no measurable improvements after direct intratumoral administration of cyanide and an anesthetic agent. Earlier animal studies showed that the effective dose of HCN gas, which rapidly diffuses the tissues, was too near the lethal dose to make HCN a clinically useful agent (20-22). Clearly, even if released, HCN is not a therapeutically acceptable or effective agent to treat cancer. Further, there is no specificity; normal as well as cancerous cells are similarly affected, and both cells contain nearly identical concentrations of the detoxifying enzyme rhodanese. The most recent mechanism holds that laetrile is a vitamin. This chronologically follows unsuccessful court battles concerning laetrile as a drug. Proponents staged a marketing coup by declaring that laetriles were vitamins, the deficiency of which leads to cancer. Therefore, daily ingestion of laetrile or "Vitamin B17" could act as a prophylactic measure to prevent cancer. This is entirely contrived, including the "antineoplastic vitamin B17" nomenclature. This product sold variously as "Bee-17" or "Aprikern" and was usually available from health-food stores. Obviously laetriles are not essential nutritional components (5). There are no disease states associated with the total dietary iack of a substance that is the prime requisite for a vitamin. This was shown in controlled dietary studies in animals (23, 24). A vitamin must also perform a unique physiologic function. In no form of life studied have the cyanoglycosides ever been shown to promote or augment any physiologic process vital to maintaining life. Indeed, the opposite appears to be true; in sufficient amounts, they can be toxic, potentially lethal. Toxicity

One to 10 grams of amygdalin have been given parenteral^ in humans, apparently without significant acute toxicities (2, 25). This indirectly suggests that there is no

significant metabolism of the intact injected glycosides. The cyanide-containing breakdown products possess well-defined toxicities, and amounts equivalent to 500 mg of mandelonitrile and 50 mg of hydrogen cyanide can be fatal (26). With oral dosing, a toxic potential is manifest. /3-Glucosidase is present in the gastric lumen, a contribution of intestinal microflora. According to one author (27), oral laetrile could be 40 times more toxic than parenterally administered doses. This is probably due to the free HCN released by the /3-glucosidase enzyme present in the gut. A review of the literature bears this out and deserves some attention. In 1964, a Turkish paper reported nine cases of cyanide poisoning, with two fatalities, from apricot-pit ingestion during the period 1957-1962 (28). The deaths and illnesses showed classic signs of cyanide intoxication— vomiting followed by a lethargic state, progressing to a comatose, moribund condition. Although eating apricot seeds is culturally accepted in Turkey, it is common knowledge by the adult population that no more than eight to 10 seeds should be ingested at a time. Apparently, exceeding this amount often results in uncomfortable effects (28). In the United States it was recognized early that apricot kernels could pose a toxic potential for those involved in the processing of the kernels (29). Procedural safeguards are now routinely employed for workers in processing plants. The world literature contains reports of toxicity from related fruit pit and berry ingestions. The offending agents, which contain cyanogenic glycosides, were ground peach seeds (30, 31) and wild chokeberry pits (32). Other reports of toxic outcomes include several in California alone of cyanide toxicity from the ingestion of apricot kernels purchased as "health foods" (33-35). In Israel a 3-year-old child ingested about 15 apricot kernels with a near-fatal outcome (36). A recent death has been reported in a 10-month-old infant in Buffalo, New York (37). Up to five 500-mg laetrile tablets obtained in Mexico belonging to the infant's father, a cancer patient, were accidentally ingested. Death occurred several hours after ingestion, and blood analysis confirmed a high level of cyanide. The injection of laetriles is also not without acute adverse effects, including fever, hypotension, rashes, dizziness, headache, vomiting, diarrhea, and, most recently, difficulties in eye movement and weakness in the arms and legs (38). In testimony given 12 July 1977, Dr. Joseph F. Ross (UCLA School of Medicine) documented 37 cases of poisoning and 17 deaths from laetrile and cyanide-containing fruit kernels based on cases collected from the United States and six other countries (11). Chronic cyanide toxicity is relatively common in Nigeria, Jamaica, and Malaya from dietary ingestion of cassava beans. These beans contain the cyanogenic glycoside linamarin, a close chemical relative to amygdalin. The disease syndrome is seen more frequently in processors and farmers of the bean. Apparently, thousands of perDorrandPaxinos

• Laetrile

Downloaded From: by a University of California San Diego User on 03/19/2017

3 9 1

sons eat the bitter tasting cassava as part of their diet. Thus there is sufficient documentation of the toxic potential of ingesting kernels containing cyanogenic glycosides. Practitioners must be aware of the signs, symptoms, and treatment of cyanide toxicity. As little as five of the "Aprikern" or "Bee-17" tablets of laetrile can be fatal in a child (37). Certainly if the use of laetriles becomes more widespread, the frequency of toxic ingestions would be expected to increase. (See Addendum.) Signs and Symptoms of Cyanide Poisoning

The signs and symptoms of cyanide poisoning have been well described and were evident in previously reported cases (33-36, 39). Graham and colleagues (40) have recently reviewed cyanide toxicity and described a case complicated by lactic acidosis and pulmonary edema. Toxic symptoms generally appear from l/2 h to 1 h after ingestion, the delay probably due to transit of the material into the intestine. (The reaction liberating H C N is known to occur more rapidly in an alkaline environment.) Hydrolysis can be completed, however, after only 10 minutes (41). The symptoms generally progress rapidly from giddiness to headache, nausea and forceful vomiting, palpitations, dyspnea leading to convulsions followed by paralysis, and finally coma. The central stimulation is described as fleeting, if noted at all. Depression, however, is always encountered. In the terminal phase, the patient can experience "cyanide" convulsions, actually anoxic in origin. The breath, vomitus, and body tissues will have a characteristic musty odor of almonds, although many persons, especially males, reportedly are not able to detect this. According to Graham and associates (40), lactic acidosis invariably occurs after significant ingestions and correlates to a widened anion gap as well as to severity of the ingestion. In the case described by Graham and co-authors, pulmonary edema was also seen. Patients commonly appear hyperthermic and diaphoretic. There are characteristic early and late cardiovascular and respiratory symptoms (42). Initially, there may be tachypnea and dyspnea with hypotension and reflex bradycardia. Sinus arrhythmia by AV nodal or idioventricular mechanisms may then be noted. This initial phase is probably both directly and indirectly due to cyanide stimulation of carotid and central respiratory receptors. In the second late phase of acute ingestion, profound respiratory depression ensues, and tachycardia or bradycardia and hypotension are present. Cardiac manifestations during this phase include ventricular ectopy and an abnormal, usually shortened, QRS complex, often with T waves originating high on the R. Very late presenting cyanide toxicity is differentially characterized by bradycardia and the lack of cyanosis, despite inadequate ventilation. If untreated, doses of 50 to 200 mg of oral H C N can be lethal. Death usually occurs by respiratory rather than cardiac arrest (39). Pijoan (32) found the H C N content of 100 g of moist cultivated apricot seeds to be 8.9 mg, of 100 g of wild Turkish varieties 217 mg, and of cultivated peaches 88 mg. We have found the average weight of a 392

commercial apricot seed to be about 610 mg. This roughly extrapolates to 0.054 mg of H C N per seed. Tablet forms of amygdalin then have the potential of providing about 28 mg of H C N per 500 mg of product. The basic metabolic lesion created by cyanide has been described as "internal asphyxia" (41) that poisons the cytochrome oxidase, respiratory enzyme system. Ironically, the bulk of hemoglobin remains saturated with oxygen as individual cells become paralyzed, unable to exchange gases. The venous Po 2 rises, and the venous blood can therefore appear bright red. Cyanosis again is not prominent in toxic ingestions even as respiration becomes increasingly labored. If supportive treatment is not instituted, death results. Chronic poisoning consists primarily of slowly developing neuropathies with ataxia and even blindness. Characteristic lesions may also affect the skin and mucous membranes as well as optic, spinal, and auditory nerves (43). Treatment

Acute toxic ingestions must be recognized and treated at an early stage. The treatment of toxic amygdalin ingestion is identical to cyanide intoxication. Gastric lavage and respiratory support are imperative if the patient is comatose. Oxygen is beneficial (44), along with judicious use of sodium bicarbonate (40). Most sources recommend that vomitus and blood samples be obtained for spectroscopic analysis both for diagnostic and medico-legal reasons. Lee-Jones, Bennett, and Sherwell (45) describe a rapid qualitative cyanide test using ferrous sulfate reduction. Toxic blood cyanide levels are those greater than 0.2 jug/ml (45). Fatalities have been reported at levels greater than 3 jag/ml. The general principle of therapy is to enhance the activity of the body's major enzymatic detoxification apparatus, as described by Chen and Rose (46). This is accomplished by giving a nitrite by inhalation or injection to create a methemoglobinemia that favors a stable cyanohemoglobin complex. This is followed by an injection of sodium thiosulfate to furnish sulfur for the tissue enzyme rhodanese (thiosulfurtransferase). This enzyme converts cyanide to the much less toxic form, thiocyanate, which is excreted in the urine. The commercial Lilly Cyanide Poisoning Kit, No. M-76, (Eli Lilly & Co., Indianapolis, Indiana) offers a convenient treatment package containing amyl nitrite and sodium thiosulfate. The other known physiologic routes of cyanide elimination—pulmonary exchange, binding by cysteine and hydroxycobalamin— are easily saturated in toxic overdoses. Alternate experimental antidotes include various cobalt salts such as cyanide chelating agents (47). Hydroxycobalamin (Vitamin B12a) has been an especially effective cyanide chelator in animal and human studies (48). In Europe good therapeutic responses have been noted with Kelocyanor® (cobalt-ethylenediaminetetra-acetate). Another product only available in Europe, aminophenol, is said to generate methemoglobin more predictably than nitrites, which have an inherent risk of severe methemoglobinemia. Occasionally, extreme hypotension from ni-

September 1978 • Annals of Internal Medicine • Volume 89 • Number 3

Downloaded From: by a University of California San Diego User on 03/19/2017

trites may require pressor therapy. Excess nitrite therapy may be enzymatically reversed by injection of methylene blue, 1 to 2 mg/kg body weight intravenously over 5 to 10 minutes (repeat if necessary) (42). Normally, methemoglobin is rapidly converted by erythrocyte metabolism to the functional (reduced) state. Graham and colleagues (40) have advocated the use of supportive care with oxygen along with intravenous hydroxycobalamin or sodium thiosulfate as the therapy of choice. However, this has not yet been widely accepted. For less severe intoxifications, patients should be given ipecac or some other emetic because a large amount of cyanide can be recovered sometime after ingestion (39). Lavage with potassium permanganate solution, 0.1% or 1:5000, or 1% hydrogen peroxide has been recommended. Activated charcoal is not indicated because it does not absorb cyanide (41). In adults, doses of up to 0.5 g of sodium nitrite intravenously (10 ml of a 3 % solution given at 2.5 to 5 ml/minute) or by inhalation, or amyl nitrite for 15 to 30 seconds followed by 10 to 25 g of sodium thiosulfate solution (10% to 25%) intravenously have been used successfully. A pediatric dosage nomogram based on weight (kg) and hemoglobin concentration is shown in Arena's book (41). Clinical Studies

To date, there have been no good clinical studies of laetrile in man. Again, much must be drawn from inference and anecdotes. Most of the reported studies have appeared in foreign sources (49-51). A lone American paper by Morrone (25) describes 10 patients (five male and five female) with advanced inoperable cancers (Hodgkin's, breast, lung, prostate, and pancreas) who were given an average of 130 1-g injections over an average of 17 weeks. Although no long-term follow-up results are reported, the author did note that the 10 patients on the average felt better, had increased appetite and muscle tone, and required substantially less analgesics than before laetrile therapy. The report failed to consider the placebo effect known to occur in cancer patients requiring narcotic analgesics (52). It would also have been interesting to know how many of the patients died from their disease during the study. A California retrospective study, with many inherent design flaws, alluded that laetriles are exceptionally poor anticancer agents (2). In that study group, a wide variety of tumors was included, and at follow-up only one patient was alive and without disease. The initial diagnosis on this patient was unconfirmed by biopsy. The reports in the foreign literature are no more satisfactory in design and validity. They all lack the essential criterion of good study design and possess many other deficiencies. The Philippine reports (49, 50) offer limited anecdotal evidence of laetrile effectiveness with neither well-defined clinical end-points nor meaningful followup. Interestingly, there have been no reports on laetrile since the late 1960s from these originally enthusiastic foreign authors. Laboratory Studies

Data on laetrile support its total lack of effect in every

in-vitro and in-vivo animal test-system employed (1, 6, 21, 53-55). This was evident to German and American researchers in the early 1900s (6, 21). They abandoned work with these agents because they were nonselectively toxic and ineffective as anticancer agents. Levi and co-workers (1) in 1965 found no significant effects on inhibition of D N A , RNA, or protein synthesis from amygdalin or sodium cyanide on four primary human tumors in vitro and three in-vivo rodent ascites tumors. However, the 0.5% phenol preservative in the Canadian laetrile preparation did show positive D N A inhibition in the assay. Similarly the in-vivo animal studies by the California Cancer Commission (2) showed no antitumor effects, except that control mice lived longer than those treated with sublethal laetrile doses. The findings of Dr. Sugiura at Sloan-Kettering Hospital, although unpublished, also reveal the same pattern of noneffectiveness. Intraperitoneal doses of 1 to 2 g/kg of amygdalin were injected in mice capable of developing spontaneous mammary tumors in response to a carcinogen. Preliminary results suggested a greater response (decreased pulmonary metastases) in the treatment group, but at the completion of follow-up trials no significant differences in the two groups were noted. Later work by Dr. Martin at the Catholic Medical Center in Queens, New York, reaffirmed laetrile's ineffectiveness under an identical testing protocol (27). There have been two recent animal studies contracted by the National Cancer Institute as part of a routine activity screen for a new anticancer agent (53, 54). Even with the addition of /3-glucosidase to the regimen, no increased life span of 25% or more was reported from amygdalin in a wide variety of murine tumors tested. (An increased life span of 25% is considered a very liberal figure.) Curiously, these studies again showed that control mice lived longer than amygdalin-treated mice. The addition of /3-glucosidase added no therapeutic enhancement; indeed, it lowered the toxic or lethal dose requirement in both studies. The significance of this, however, was not reported. Hill and associates (55) have reported no effects from amygdalin in two systems, BW 5147 A K R leukemia and B16 melanoma, at doses from 50 to 5000 mg/kg. Campbell (56) has reported that laetrile is ineffective when used as an antischistosomatic agent. Clearly, there is a preponderance of reported scientific investigations that show laetriles to be ineffective and potentially toxic agents in the treatment of cancer. To believe that these agents could be beneficial in light of these studies involves the notion that current screening procedures themselves are unreliable in sifting out viable new anticancer agents. However, the screening process has generally worked very well in predicting clinically useful anticancer agents from positive laboratory work (57, 58). History

Amygdalin was first used as an anticancer agent in Germany in 1892 but was abandoned due to lack of specific canceristatic effects and marked toxicity (6). In the early 1900s, Ernest T. Krebs, a physician working on a Dorr and Paxinos • Laetrile

Downloaded From: by a University of California San Diego User on 03/19/2017

3 9 3

synthetic bourbon flavoring, "rediscovered" amygdalin and began using it in rats and then in cancer patients in California (59). He purportedly noted anecdotal improvement in animals and in a few humans but halted experiments, apparently due to peer pressure concerning toxicity (6, 60). In the late 1940s, his son, Mr. E.T. Krebs, Jr., synthesized a "new, nontoxic" form of amygdalin, laetrile. This was patented in 1949 (Patent # 2 464 240). In the 1950s, Krebs became closely aligned with the John Beard Memorial Foundation, which at that time was supporting a so-called unitarian theory of the origin of neoplasms (61, 62). Briefly, this theory suggested that all cancers arise out of misguided trophoblastic cells. In Montreal, the Andrew McNaughton Foundation was also operating to distribute laetrile information and a "sterile preparation" to anyone requesting it. In 1953, the California Cancer Commission initiated an uncontrolled in-vivo study of laetrile in 44 outpatients of five Southern California physicians (2). Krebs' involvement in this activity was to the extent of initially agreeing to supply the laetrile, but he later withdrew because a designate from his group could not direct the study. By 1959, California had passed a law specifically aimed at laetrile, making medical quackery a felony rather than a misdemeanor. In 1962, the laetrile proponents pleaded guilty to violations of the then new FD&C (Kefauver Drug Safety) amendments (63). By 1965, the proponents had agreed to a permanent injunction that prohibited further distribution of the drug. However, 1 year later, the same proponents pleaded guilty to violations of the injunction (27). In 1970, the FDA, within 1 month, both awarded and repealed an investigational new drug application for laetrile that would have allowed access to the drug by qualified researchers. The F D A cited serious clinical shortcomings in the application as the reason for the repeal. A significant amount of notoriety was generated by this action. In 1971, representatives of the American Medical Association, FDA, and American Cancer Society reviewed available evidence of laetrile effectiveness and could find no valid data supporting the claims. In 1973, the National Cancer Institute contracted two studies of laetrile in animals, one at Sloan-Kettering Hospital in New York and the other 1 year later at Catholic Medical Center, Queens, New York. A now infamous incident at Sloan-Kettering occurred when an interdepartmental memo was "leaked" in Science (64) and the St. Louis Globe-Democrat (65). In a preliminary report, Dr. Kanematsu Sugiura had noted that control mice had a 78% incidence of lung metastases whereas laetriletreated mice had only a 17% incidence. This, however, could not be repeated either by Sugiura or in the followup study by Dr. Martin of the Catholic Medical Center study group. Both investigators believed further work with the compound was unjustified but did not report their negative results. After this work, there was an upsurge in interest in laetrile, and a few well-controlled animal studies were conducted, again with negative results (53-56). By 1975, 394

the proponents were claiming the drug was a prophylactic antineoplastic vitamin, B17. In the same year, California placed an injunction against General Research Laboratories to halt further distribution of the "vitamin." The court found that the item was both adulterated and misbranded as a food and a drug. This action was based on an unallowable concentration of cyanide in a food, a lack of substantiation as a vitamin, and a danger in that use might forestall more effective alternative therapy for cancer. Legal-Judicial Activities

Since Krebs* introduction and promotion of laetrile for cancer treatment in the early 1950s, various levels of success in achieving active and sympathetic support have been attained. The McNaughton Foundation is generally credited with maintaining interest in laetrile since the late 1950s. However, only recently has significant progress through legislative actions been achieved. It may be more than coincidental that this was due to a change in tactics by laetrile supporters. Four groups (National Health Federation, International Association for Cancer Victims and Friends, Cancer Control Society, Committee for Freedom of Choice in Cancer Therapy) working in alliance with the McNaughton Foundation lobbied extensively for introduction and passage of bills relating to laetrile through the state legislatures. The medical issues thus took on a political flavor. Proponents' arguments included denunciations of the medical establishment and governmental intervention into private affairs. Individual "freedom of choice" became a favorite rallying cry. As a consequence, 13 states—Alaska, Arizona, Delaware, Florida, Illinois, Indiana, Louisiana, Nevada, New Hampshire, Oklahoma, Oregon, Texas, and Washington—have passed bills that, to varying degrees, remove many of the legal sanctions against laetrile use. The diversity of the enabling legislation emphasizes the uncertainty on how to deal appropriately with this issue on a rational scientific basis. Individual applications of the enacted bills are subject to interpretation. Although some states may call laetrile a food, it can be construed as a drug by the individual states' regulatory boards. These boards would have legal recourse to regulate the item if not in compliance with current food and drug laws of the state. A federal court precedent has already been set in this interpretation (66). Interestingly, similar bills have been consistently defeated in California. California is the home of the strongest pro-laetrile lobbying committees and, historically, is the state where the greatest numbers of patients have been treated, both for cancer with laetrile and for cyanide toxicity from fruit-pit ingestions. This ambivalent trend is continuing, and a number of states that have "legalized" laetrile are now actively considering repeals. None have instituted meaningful standards for its manufacture and use or other controls. These recent decisions suggest that most of the medical community has rejected the value of laetrile but the nonmedical community has not. Through a well-organnized effort, the laetrile movement has gained some polit-

September 1978 • Annals of Internal Medicine • Volume 89 • Number 3

Downloaded From: by a University of California San Diego User on 03/19/2017

ical support and momentum. Faced with this reality, it is no longer reasonable to ignore the laetrile issue, especially if one practices in a state that has passed legislation on this drug. Of much broader concern is the impact that laetrile legalization will have on the delivery of health care in this country. In essence, legalization of an unproven and ineffective drug circumvents the purpose of the existing drug laws, which serve to protect the public. Laws that took decades to implement may be meaningless. Products of unproven effectiveness may once again be manufactured and distributed. Interestingly Mexico, the country considered the major source of laetrile supply for American citizens, has recently moved to terminate its production because of laetrile's apparent lack of value in cancer therapy (38). Availability

The FDA's response, from a legal standpoint, is that it will continue to take regulatory action against commercial distribution of laetrile when federal laws are violated. States that have legalized laetrile use must produce the drug completely within their state boundaries, including obtaining the raw product, if they are to be in compliance with federal laws. This prevents any massive influx of laetrile into the state from other countries and other "legalized" states. Until in-state manufacturers are established, laetrile will not be generally available, and importation will probably continue on an individual basis. Nevada legislators have frankly admitted that laetrile will probably not be available until far into 1978 at the earliest. In the Rutherford versus the United States case in February 1977, the F D A clearly delineated their stand that laetrile is considered to be "a new drug" (not a food) and that it is not exempt from existing premarket approval requirements (the "grandfather clause") (66). This Kansas case sought court approval for a resident to legally obtain laetrile. The Bohannon decision that followed (Oklahoma) specifically facilitated the ability of any terminally ill patient to legally obtain the drug (66). Thus legal avenues to drug supply in special cases have not been barred by the federal agencies. Since laetrile may be considered a drug, as denned by the states' medical and pharmaceutical regulating bodies, specific guidelines as to its manufacture, labeling, distribution, prescribing, and administration must be established. This will probably be done through the individual state's public health, medical, or pharmaceutical boards and will require adherence to the individual state's health professionals practice acts. In essence, these are procedures similar to those in use for any drug. Additional restrictions may be dictated by the individual state's governing boards. Once these guidelines are defined, establishment of a legal manufacturer(s) within the state can be expected. Individual state standards will probably follow the regulations under the Federal Food, Drug and Cosmetic Act for current Good Manufacturing Practice (67). These regulations deal with the manufacture, processing, packaging, or holding of a product to insure that it meets

requirements for safety, identification, strength, and quality and purity characteristics. The standards should provide adequate control over the production, distribution, labeling, and storage of laetrile. However, they will not provide adequate information on dosage and administration since all of the clinical studies have essentially determined that laetrile has no effect. Therefore, dosage recommendations will probably be determined from data on its uncontrolled clinical use. One brochure recommends that laetrile be administered intravenously, 6 g daily for 2 to 3 days, although 9 g intravenously daily for 2 weeks is not uncommon (68). This can then be tapered, based on how patients "feel," over a 10-week or longer period to 3 g once a week. Patients may then continue this regimen or be taken off it completely. In conjunction with the intravenous regimen, oral tablets are recommended. Again, the dosage varies depending on the intensity of the intravenous regimen. It is suggested that the oral tablets be taken for the remainder of the patient's life. It remains conjecture at this time to attempt to predict what ramifications will occur in the individual states as a result of legalization of laetrile. Conceivably, as a result of some of the legislative activities, "laetrile clinics" will be established. These would specialize strictly in treating cancer victims with laetrile and other unfounded modes of therapy. Cancer victims dissatisfied with their current care will make up a large segment of the patients seeking treatment at these centers. Another large portion of patients would probably be those referred by physicians who have tried without success all the current accepted therapies and accept that a trial with laetrile may be of some psychological benefit. Perhaps the most significant potential population of patients, however, would be newly diagnosed patients bypassing established medical treatment schemes. Most likely, the recent legislative activities will have minimal impact due to the lack of objective scientific data on which the regulatory boards can base their standards. The present level of activities with laetrile will probably continue until interest wanes as the negative scientific findings gain more notoriety. Ethical and Liability Issues

So far, we have discussed the practical aspects of the recent legalization of laetrile. We have not yet considered the medical ethics involved with this issue. Additionally, there has been concern about the liability the health practitioner will incur when administering a medically unapproved drug. Practitioners should take note of the recent decision by a quasi-state medical insurance agency in Nevada. They stated they would not insure physicians against laetrile use. The recent legislative activity gives the medical professional the opportunity to encourage, discourage, or ignore the use of laetrile for cancer therapy. The patient who is now aware of his "rights" for laetrile therapy can no longer be ignored. The physician must assure the patient that all of the currently accepted modes of cancer therapy have been tried, and thus eliminate the possibility of a patient delaying potentially beneficial treatment in Dorr and Paxinos • Laetrile

Downloaded From: by a University of California San Diego User on 03/19/2017

3 9 5

lieu of laetrile therapy. The use of laetrile must be of no detriment to the patient. Each health professional must make his own determination on the ethical issues. Our intentions here were not to persuade nor dissuade but rather to provide comprehensive information on the subject so that one could make his own interpretations. The final decisions will be the result of a mutual understanding between the individual practitioner and his patient. • Requests for reprints should be addressed to Robert T. Dorr, R.Ph.; University of Arizona Health Sciences Center, 1501 N. Campbell; Tucson, AZ 85724. Received 7 December 1977; revision accepted 1 May 1978.


Since preparation of this paper, two additional reports of laetrile toxicity, including one case associated with rapid death, have been published (69, 70).


25. 26.

27. 28. 29. 30.








treatment of cancer with "Laetriles." Calif Med 78:320-326, 1953 3. D A V I G N O N JP, TRISSEL LA, K L E I N M A N LM: Pharmaceutical assess-

7. 8. 9. 10. 11. 12. 13. 14.

15. 16.

17. 18. 19.


21. 22.

ment of amygdalin (Laetrile) products. Cancer Treatment Rep 62:99104, 1978 STECHER PG (ed.): The Merck Index. An Encyclopedia of Chemicals and Drugs, 8th ed. Rahway, New Jersey, Merck & Co., Inc., 1968, pp. 76, 606. GREENBERG DM: The vitamin fraud in cancer quackery. West J Med 122:345-348, 1975 VIERHOVER A, MACK H: Biochemistry of amygdalin. Am J Pharm 107:397-450, 1935 LIEBIG J, W O H L E R F: Uber die Bildung des Bittermandelols. Annalen der Chemie und Pharmacie 22:1 -24, 1837 ROBIQUET, BOUTRON: Les amandes ameres et l'huile volatile qu' elles fournissent. Ann Chim Phys 44:352-382, 1830 V A N M E T E R CT, G E N N A R O AR: Natural products, in Remington's Pharmaceutical Sciences, 14th ed. Easton, Pennsylvania, Mack Publishing Co., 1965, pp. 474-475 See Reference 4, pp. 76, 606 Statement by RICHMOND J (Assistant Secretary for Health). HEW News P77-30:1-7, 1977 H O L D E N C: Laetrile: "quack" cancer remedy still brings hope to sufferers. Science 193:982-985, 1976 CONCHIE J, FINDLAY L, LEVVY GA: Mammalian glycosidases. Distribution in the body. Biochem 7 71:318-325, 1959 G A L E M , F U N G F-H, GREENBERG DM: Studies on the biological action of malononitriles. II. Distribution of rhodanese (transulfurase) in the tissues of normal and tumor-bearing animals and the effect of malononitriles thereon. Cancer Res 12:574-579, 1952 FISHMAN WH, ANLYAN AJ: The presence of high ^-glucuronidase activity in cancer tissue (letter). J Biol Chem 169:449-450, 1947 FISHMAN WH, ANLYAN AJ: Comparison of the /3-glucuronidase activity of normal, tumor, and lymph node tissues of surgical patients. Science 106:66-67, 1947 BICKIS IJ, QUASTEL JH: Effects of metabolic inhibitors on energy metabolism of Ehrlich ascites carcinoma cells. Nature 205:44-46, 1965 WARBURG O: Metabolism of Tumours. London, Constable and Co. Ltd., 1930 BROWN WE, W O O D CD, SMITH AN: Sodium cyanide as a cancer chemotherapeutic agent. Laboratory and clinical studies. Am J Obstet Gynecol 80:907-918, 1960 C L O W E S GHA: A study of the influence exerted by a variety of physical and chemical forces on the virulence of carcinoma in mice. Br Med J 4:548-554, 1906 KARCZAG I: Die Chemotherapie des Mausekarzinomas durch Fermentgifte. Archiv Exper Zellforsch 6:178-181, 1928 PERRY IH: The effect of prolonged cyanide treatment on body and tumor growth in rats. Am J Cancer 25:592-598, 1935

23. G R E E N S T E I N JP, BIRNBAUM SM, W I N I T Z M, O T E Y MC: Quantitative

nutritional studies with water-soluble, chemically defined diets. I. Growth, reproduction and lactation in rats. Arch Biochem Biophys 72:396-416, 1957 396


CALIFORNIA: Cyanide poisoning from apricot kernels. Calif 51, 1975

of its physicochemical and biochemical properties. Can Med Assoc J 92:1057-1061, 1965



CALIFORNIA: Cyanide poisoning from the ingestion of apricot kernels. CalifMorbidity 45, 1975

1. L E V I L, F R E N C H WN, BICKIS I J, H E N D E R S O N IWD: Laetrile: a study



CALIFORNIA: Cyanide poisoning from the ingestion of apricot kernels. Calif Morbidity 34, 1972



J E A N N I N J, B E R R O D R, L E M A I R E , B A Z I N : Intoxication grave survenue

chez une enfant apres ingestion den noyaux de peches. Lyon Med 93:785-793, 1961 31. IOANID N, BORS G: Les empoisonnements par les glucoside cyanogenetiques et leur differenciation de ceux dus a l'acide cyanhydrique ou a ses sels. Ann Med Leg 41:275-279, 1960 32. PIJOAN M: Cyanide poisoning from choke cherry seed. Am J Med Sci 204:550-553, 1942



BIRNBAUM SM, G R E E N S T E I N JP, W I N I T Z M: Quantitative nutritional

studies with water-soluble, chemically defined diets. II. Nitrogen balance and metabolism. Arch Biochem Biophys 72:417-427, 1957 M O R R O N E JA: Chemotherapy of inoperable cancer. Exp Med Surg 20:299-308, 1962 DREISBACH RH: Handbook of Poisoning: Diagnosis and Treatment, 7th ed. Los Altos, California, Lange Medical Publications, 1971, pp. 218220 EYERLY RC: Laetrile: focus on the facts. CA 26:50-54, 1976 SAYRE JW, KAYMAKCALAN S: Cyanide poisoning from apricot seeds among children in central Turkey. N Engl J Med 270:1113-1115, 1964 GRABOIS B: Exposure to hydrogen cyanide in processing of apricot kernels. Monthly Rev NY Department Labor 33:33-36, 1954



G U N D E R S AE, A B R A H A M O V A, W E I S E N B E R G E: Cyanide poisoning

following ingestion of apricot (Prunus armeniaca) kernel. / Israel Med Assoc 76:536-538, 1969 37. H U M B E R T JR, TRESS JH, BRAICO KT: Fatal cyanide poisoning: accidental ingestion of amygdalin (letter). JAMA 238:482, 1977 38. L E W I S JP: Laetrile. West J Med 127:55-62, 1977 39.

GOSSELIN RE, H O D G E HC, S M I T H RP, G L E A S O N M N : Cyanide, in

Clinical Toxicology of Commercial Products, 4th ed. Baltimore, Williams & Wilkins, 1976, pp. 105-112 40.

41. 42. 43.



G R A H A M DL, L A M A N D, T H E O D O R E J, R O B I N E D : Acute cyanide

poisoning complicated by lactic acidosis and pulmonary edema. Arch Intern Med 137:1051-1055, 1977 A R E N A JM: Cyanide, in Poisoning: Toxicology, Symptoms, Treatments, 3rd ed. Springfield, Illinois, Charles C Thomas, 1974, pp. 210-215 GOLDFRANK L, KIRSTEIN R: The tea party. Hosp Physician 13(4):3033, 1977 OSUNTOKUN BO: Ataxic neuropathy associated with high cassava diets Interdisciplinary in West Africa, in Chronic Cassava Toxicity: An Workshop. Monograph IDRC-OlOe. London, International Developmental Research Centre, 1973, pp. 127-138 ISOM GE, W A Y JL: Effect of oxygen on cyanide intoxication. VI. Reactivation of cyanide-inhibited glucose metabolism. J Pharmacol Exp Ther 189:235-243, 1974 L E E - J O N E S M, B E N N E T T MA, S H E R W E L L JM: Cyanide self-poisoning.

Br Med J 4:780-781, 1970 46. C H E N K K , R O S E CL: Treatment of acute cyanide poisoning. JAMA 162:1154-1155, 1956 47. EVANS CL: Cobalt compounds as antidotes for hydrocyanic acid. Br J Pharmacol Chemother 23:455-475, 1964 48.

P O S N E R MA, T O B E Y RE, M C E L R O Y H: Hydroxycobalamin therapy of

cyanide intoxication in guinea pigs. Anesthesiology 44:157-160, 1976 49. NAVARRO MD: The mechanism of action and therapeutic effects of laetrile in cancer. JPhilipp Med Assoc 33:620-627, 1957 50. NAVARRO MP: Laetrile therapy in cancer. Philipp J Cancer 4:204-209, 1962 51. TASCA M: Clinical observations on the therapeutic effects of a cyanogenetic glucuronoside (sic) in cases of human malignant neoplasms. Gazz Medltal 118:153-159, 1959 52.

M O E R T E L CG, T A Y L O R W F , R O T H A, T Y C E FAJ: Who responds to

sugar pills? Mayo Clin Proc 51:96-100, 1976 53. LASTER WR J R , SCHABEL FM J R : Experimental studies of the antitumor activity of amygdalin M F (NSC-15780) alone and in combination with /3-glucosidase (NSC-128056). Cancer Chemother Rep 59:951-965, 1975 54. WODINSKY I, SWINIARSKI J K : Antitumor activity of amgydalin M F (NSC-15780) as a single agent and with b-glucosidase (NSC-128056) on a spectrum of transplantable rodent tumors. Cancer Chemother Rep 59:939-950, 1975 55.

H I L L GJ II, S H I N E TE, H I L L HZ, M I L L E R C: Failure of amygdalin to

arrest B16 melanoma and BW5147 A K R leukemia. Cancer Res 36:2102-2107, 1976 56. CAMPBELL WC: Laetrile and schistosomiasis (letter). Science 184:588, 1974

September 1978 • Annals of Internal Medicine • Volume 89 • Number 3

Downloaded From: by a University of California San Diego User on 03/19/2017

57. GOLDIN A, SERPICK AA, M A N T E L N: A commentary: experimental

screening procedures and clinical predictability valve. Cancer Chemother Rep 50:173-184, 1966 58. G E R A N RI, GREENBERG NH, M A C D O N A L D MM, SCHUMACHER AM,

59. 60. 61. 62. 63.

ABBOTT BJ: Protocols for screening chemical agents and natural products against animal tumors and other biological systems. Cancer Chemother Rep 3(2):1-103, September 1972 ANONYMOUS: The laetrile controversy. MD 21:49-52, 1977 ANONYMOUS: Unproven Methods of Cancer Management. Laetrile. New York, American Cancer Society, Inc., 1977, pp. 139-144 BEARD J: Embryological aspects and etiology of carcinoma. Lancet 1:1758-1761, 1902 BEARD HH: A New Approach to the Conquest of Cancer, Rheumatic and Heart Diseases. New York, Pageant Press, Inc., 1958 United States of America vs. John Beard Memorial Foundation and Krebs, ET, Jr., Criminal Case No. 38179, District Court for the Northern District of California, Southern Division, 17 May 1962

64. CULLITON BJ: Sloan-Kettering: the trials of an apricot pit—1973. Science 182:1000-1003, 1973 65. TIMNICK L: Use of cancer drug: an ethical question. St. Louis GlobeDemocrat 122:15C, 28 June 1974 66. ANONYMOUS: Laetrile. Commissioners decision on status. Fed Reg 42(151):39768-39806, 1977 67. FOOD AND DRUG ADMINISTRATION: Drugs: current good manufacture, processing, packing or hold. Regulations under FD&C Act, Part 133, Title 21, Code of Federal Regulations, reprinted July 1968 68. ANONYMOUS: Metabolic therapy and laetrile in clinical applications against cancer (product brochure). Phoenix, Arizona, Rocky Mountain Pharmacal, 1977 69. SADOFF L, FUCHS K, HOLLANDER J: Rapid death associated with laetrile ingestion. JAMA 239:1532, 1978 70. SMITH FP, BUTLER TP, COHAN S, SCHEIN PS: Laetrile toxicity: a re-

port of two patients. Cancer Treat Rev 62:169-171, 1978

Dorr and Paxinos • Laetrile

Downloaded From: by a University of California San Diego User on 03/19/2017

3 9 7

The current status of laetrile.

REVIEW The Current Status of Laetrile ROBERT T. DORR, M.S., R.Ph.; and JAMES PAXINOS, Amygdalin at various concentrations and with numerous impuriti...
2MB Sizes 0 Downloads 0 Views