The Annals of Pharmacotherapy I
2005 September, Volume 39
tion to or instead of conventional medical therapies.
We describe a case of a patient who developed severe
toxicity after starting amygdalin while using a number of
other CAM therapies. This case serves to highlight the po-
tential dangers and interactions between these CAM thera-
pies. We also review the history of amygdalin use and the
evidence on its safety and efficacy in oncology.
omplementary and alternative medicines (CAMs) are
commonly used among patients with cancer in addi-
A 68-year-old female presented to the emergency department com-
plaining of dizziness and feeling unwell. She had taken her first dose (six
500-mg tablets) of amygdalin approximately 21/2 hours earlier that
evening with a dinner consisting of fish and vegetables. These tablets
had been obtained from the UK over the Internet; however, the tablets
themselves were produced in Mexico (Figure 1). She began to feel ill
within about 30 minutes after taking amygdalin.
The patient had recently been diagnosed with locally advanced (stage
T4N0M0) urothelial carcinoma of the bladder. This was initially man-
aged with chemotherapy consisting of intravenous cisplatin and gem-
citabine. As a result of prolonged myelosuppression after receiving her
first cycle, clinicians decided to discontinue chemotherapy and manage
the cancer with palliative radiotherapy. The woman’s medical history
otherwise consisted of hypercholesterolemia, osteoporosis, and a recent
deep venous thrombosis of the left leg.
She had begun taking a number of complementary preparations in ad-
dition to her conventional treatment. Her total daily intake of vitamin C
was 4800 mg. Medications included:
1. vitamin C 1000 mg 4 times daily;
2. Executive B (vitamin B supplement that also contains 250 mg of
vitamin C per tablet);
3. vitamin B625 mg/zinc 25 mg/magnesium 50 mg;
4. Bio Ace 1 tablet daily (vitamin C 550 mg, beta-carotene 3 mg, vi-
tamin E 75 IU, thiamine 10 mg, calcium pantothenate 55 mg, pyri-
doxine 25 mg, zinc amino acid chelate 25 mg);
5. Co Q Max 150 mg (naturally occurring human protein also known
6. Flor/essence 30 mL twice daily (unquantified amounts of burdock,
sheep sorrel, slippery elm, blessed thistle, brown algae, watercress,
red clover, Turkish rhubarb);
7. shark fin 500 mg/day (shark cartilage extract); and
8. warfarin 5 mg/day.
Life-Threatening Interaction Between Complementary
Medicines: Cyanide Toxicity Following Ingestion of Amygdalin
and Vitamin C
Jonathan Bromley, Brett GM Hughes, David CS Leong, and Nicholas A Buckley
OBJECTIVE: To describe a case of severe accidental cyanide poisoning following a single ingestion of amygdalin with therapeutic
CASE SUMMARY: A 68-year-old patient with cancer presented to the emergency department shortly after her first dose (3 g) of
amygdalin with a reduced Glasgow Coma Score, seizures, and severe lactic acidosis requiring intubation and ventilation. The
patient also ingested 4800 mg of vitamin C per day. She responded rapidly to hydroxocobalamin treatment. The adverse drug
reaction was rated probable on the Naranjo probability scale.
DISCUSSION: Amygdalin and laetrile (a synthetic form of amygdalin) are commonly used as complementary or alternative medicine
(CAM) for the treatment of cancer. Vitamin C is known to increase the in vitro conversion of amygdalin to cyanide and reduce body
stores of cysteine, which is used to detoxify cyanide. Amygdalin has been used for decades by patients with cancer who are
seeking alternative therapies, and severe reactions have not been reported with this dose. An interaction with vitamin C is a
plausible explanation for this life-threatening response.
CONCLUSIONS: This case highlights the fact that CAMs can produce life-threatening toxicity. This case also adds a further note of
caution, namely, the potential for serious interactions between CAMs, particularly where there is no tradition of concomitant use.
KEY WORDS: amygdalin, cyanide, laetrile, vitamin C.
Ann Pharmacother 2005;39:1566-9.
Published Online, 12 Jul 2005, www.theannals.com, DOI 10.1345/aph.1E634
Author information provided at the end of the text.
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On arrival at the hospital, the patient’s Glasgow Coma Score (GCS)
was 13 and her heart rate was 136 beats/min and regular. Soon after ar-
rival, she had 2 generalized tonic–clonic seizures, with a postictal GCS
of 5. She was intubated and mechanically ventilated with 100% oxygen.
Her blood cell count, electrolyte levels, and renal function tests were un-
remarkable aside from a white blood cell count of 5.7 × 103/mm3. The
presentation was recognized as consistent with cyanide toxicity sec-
ondary to amygdalin (Table 1).1Serial arterial blood gases after intuba-
tion are shown in Table 2. Plasma lactate concentrations are probably the
best indicator of the severity of cyanide poisoning and the response to
treatment in this case,2as no cyanide levels were available.
Activated charcoal was administered orally, and the cyanide antidote
hydroxocobalamin 5 g was infused intravenously over 30 minutes. The
patient made a satisfactory neurologic recovery over the course of the
night and was extubated the following morning. She was discharged 2
days later with no residual sequelae. The laboratory effects of cyanide
toxicity are shown in Table 2. The amygdalin preparation was sent to the
Therapeutic Goods Administration for analysis; the tablets contained the
claimed 500 mg of amygdalin per tablet. On the Naranjo probability
scale, the adverse drug reaction was rated probable.3
MECHANISM OF TOXICITY OF AMYGDALIN AND THE
INTERACTION WITH VITAMIN C
Amygdalin causes toxic effects by producing cyanide.
Cyanide inhibits mitochondrial cytochrome oxidase and,
therefore, oxidative phosphorylation.4As a consequence,
anaerobic metabolism is increased and lactic acid is pro-
duced. Notably, our patient had severe lactic acidosis on
presentation. There were no other likely explanations for
this acidosis, which resolved rapidly with hydroxocobal-
amin, a specific antidote for cyanide poisoning.
Hydrolysis of the amygdalin molecule yields up to 6%
(w/w) hydrogen cyanide (HCN), benzaldehyde, and glu-
cose.5Thus, this dose (3000 mg) of amygdalin could theo-
retically produce as much as 180 mg of cyanide, well
above the estimated potentially lethal dose of 50–100 mg.4
Hydrolysis after absorption is very low, and parenteral ad-
ministration of amygdalin rarely causes toxicity.4,6Hydrol-
ysis may occur in the gut and is promoted by β-glucosidas-
es (present in almonds and apricot kernels and produced
by some gut bacteria), heat, mineral acids, and high doses
of ascorbic acid.5β-Glucosidases are not normally abun-
dant in the upper gastrointestinal tract.
The dose used by our patient was slightly higher than
that administered in formal studies of amygdalin (usually
1.5–2 g/day).7,8At these doses, long-term use did not ap-
pear to ever cause severe cyanide toxicity. However, doses
as high as 9 g/day are recommended on some Web sites,9,10
and, as of July 1, 2005, there have been no reports of seri-
ous cyanide toxicity with oral doses <6 g.4We believe the
best explanation for her severe reaction is that “mega-dos-
es” of vitamin C (>3 g) not only might increase hydrolysis
by the above mechanism, but also markedly decrease the
body stores of cysteine, a sulfur-containing amino acid that
facilitates the detoxification of cyanide.11Cyanide is large-
ly metabolized by the abundant mitochondrial enzyme
rhodenase,4and the rate-limiting step in detoxification is
the availability of intracellular cystine and cysteine.4,12Ani-
mal studies have confirmed the greater toxicity of amyg-
dalin given with high doses of vitamin C.13
HISTORY OF AMYGDALIN USE FOR CANCER
Amygdalin is a substance found in the kernels of apri-
cots and other stone fruits. It was first isolated in 1830 by
French chemists. The suggested mechanism of amyg-
dalin’s anticancer action has changed over the years, but
probably the most widely stated claim is that neoplastic
cells are rich in an enzyme that causes amygdalin to re-
lease cyanide that kills the neoplastic cells. Non-neoplastic
cells are protected from this process by another enzyme
that renders the cyanide harmless.14There is no convincing
evidence for a selective effect on neoplastic cells.
In contrast with many CAM therapies, there is no histo-
ry of traditional ethnic use of amygdalin for cancer. The
history is dominated by quackery—extravagant and un-
supported claims based on pseudo-scientific theories and
attempts to bypass regulation by those with questionable
The Annals of Pharmacotherapy I
2005 September, Volume 39 I
Table 1. Clinical Effects of Cyanide Toxicity1
headache, tachycardia, confusion, weakness
cyanosis, coma, convulsions, cardiac arrhythmias
circulatory and ventilatory failure, cardiac arrest, death
Figure 1. The amygdalin container prepared in Mexico: note lack of prescrip-
tion, dosing instructions, and warning labels.
qualifications. In 1950, 2 Americans, Ernest T Krebs Sr.
MD, and his son, Ernest Jr., began using a “purified” ver-
sion of the drug, which they patented as laetrile for “disor-
ders of intestinal fermentation.” However, their main pro-
motion of laetrile was as an anticancer drug.14,15Krebs Sr.
worked as a pharmacist before he received his medical de-
gree in San Francisco 50 years earlier. His son referred to
himself as Dr. Krebs, but had failed medical school. He
was awarded an honorary “doctor of science” degree by
the American Christian College in Oklahoma after deliver-
ing a lecture on laetrile; interestingly, the college had no
science department. In 1970, in an attempt to circumvent
Food and Drug Administration regulations, Krebs claimed
that laetrile was in fact a vitamin (B17), as vitamins are not
subject to the same safety and efficacy requirements as
The ensuing years have seen the battle for laetrile play
out in food and drug regulation, the courts, and the news-
papers. It is effectively banned in the US, but available in
special clinics in Mexico, the original source of our pa-
tient’s medication. While there is no evidence of the use of
laetrile in Australia in Krebs’ era, the increased availability
of pharmaceuticals through the Internet seems to have giv-
en it greater accessibility in our region.
Despite an absence of scientific evidence, it has been
apparently easy to raise some public support for laetrile
among cancer support groups. Support is fueled by anec-
dotal cases of miraculous results from the drug that do not
hold up to scrutiny. For example, a woman set up the Inter-
national Association of Cancer Victims and Friends in
1963 to support its use, convinced that it had saved her life.
She had undergone a radical mastectomy for early breast
cancer and also had received treatment with laetrile. The
fate of actor Steve McQueen, also a strong advocate of the
drug, is perhaps more telling. He travelled to Mexico to
undergo treatment with laetrile at a clinic in 1980 and died
within a few weeks of commencing treatment.14
LACK OF EVIDENCE FOR EFFICACY OF AMYGDALIN
There has never been any scientific support for amyg-
dalin, but studies have been performed on a number of oc-
casions largely in response to its use. In 1962, the Califor-
nian Cancer Advisory Council reviewed 100 case histories
and decided that none showed any evidence that laetrile
was beneficial against cancer. They recommended that
regulations be issued to ban the use of laetrile and similar
agents for the treatment of cancer.14
In 1982, the National Cancer Institute undertook a
Phase II clinical trial using patients taking amygdalin.7
Most of the patients had breast, colon, or lung cancer.
Amygdalin was administered by injection for 21 days, fol-
lowed by oral maintenance therapy. Vitamins and pancre-
atic enzymes were also given, and dietary changes were in-
stituted. During treatment, cancer progressed in 54% of the
patients, and only one partial response was seen among
175 patients who were evaluated for tumor response. Fur-
thermore, several patients were found to have symptoms
suggestive of mild cyanide toxicity, significant blood lev-
els of cyanide, or both.
WIDESPREAD USE OF CAM THERAPIES
The use of CAM therapies in addition to or instead of
conventional therapies has continued to rise. Large num-
bers of patients are taking one or more nonprescribed med-
ications, and many are not reporting these at consultation
with healthcare providers. In the US, 34% of survey re-
spondents admitted using alternative therapies in 1990,
with this figure rising to 42% in 1997.16In addition, it was
found that disclosure of these medications to physicians
was only 38% and 40%, respectively. Previous reviews
have highlighted the issue of interactions betweens drugs
and CAM therapies,17but the issue of interactions between
CAM therapies has received little attention.
We postulate that our patient inadvertently increased her
risk of cyanide toxicity by coingestion of amygdalin with
megadoses of vitamin C. This case also highlights the fact
that CAM therapies can have serious and life-threatening
toxicities and further refutes the commonly held myth that
they are universally safe. Clinicians should be aware of the
potential for serious interactions between different CAM
therapies, particularly where there is no long tradition of
safe concomitant use.
Jonathan Bromley MBChB, Toxicology Registrar,
Department of Clinical Pharmacology and Toxicology,
The Canberra Hospital, Garran, Australia
Brett GM Hughes BSc (Med) MBBS (Hons), Medi-
cal Oncology Registrar, Department of Medical On-
cology, The Canberra Hospital
David CS Leong MBBS FRACP, Consultant Medi-
cal Oncologist, Department of Medical Oncology, The
Nicholas A Buckley MD FRACP, Consultant Toxicol-
ogist and Clinical Pharmacologist, Department of Clinical
Pharmacology and Toxicology, The Canberra Hospital
Reprints: Dr. Bromley, Department of Clinical Phar-
macology and Toxicology, The Canberra Hospital, Yam-
ba Dr., Garran, Australia, ACT 2606, fax 02 62813935,
The Annals of Pharmacotherapy I
2005 September, Volume 39
J Bromley et al.
Table 2. Serial Blood Gas Analysis on Presentation
to the Emergency Department
10 min After
PCO2(35–45 mm Hg)
Base excess (–2.4 to 2.4 mEq/L)
Lactate (4.5–18 mg/dL)
Cyanide Toxicity Following Ingestion of Amygdalin and Vitamin C
The Annals of Pharmacotherapy I
2005 September, Volume 39 I
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OBJETIVO: La amigdalina y el laetrilo (una forma sintética de
amigdalina) se usan comúnmente como medicina complementaria o
alternativa en la terapia contra el cáncer. Describimos un caso de
envenenamiento accidental severo por cianuro tras la ingesta de
amigdalina para propósitos terapéuticos.
RESUMEN DEL CASO: Una paciente de cáncer de 68 años de edad se
presentó a la sala de emergencias tras la primera dosis de amigdalina
complementaria con una puntuación reducida en la escala de coma de
Glasgow, convulsiones, y acidosis láctica severa, requiriendo intubación
y ventilación. La paciente también consumía 4800 mg de vitamina C
diariamente. Ella respondió rápidamente a tratamiento con
hydroxicobalamina. La reacción adversa fue catalogada como
“probable” en la escala de probabilidad de Naranjo.
DISCUSIÓN: Es sabido que la vitamina C aumenta la conversión invitro de
amigdalina a cianuro y reduce el almacenaje corpóreo de cisteína, la
cual se utiliza para detoxificar el cianuro. La amigdalina ha sido
utilizada por décadas por pacientes de cáncer buscando terapias alternas
sin que se haya reportado reacciones severas con esta dosis. Una
interacción con la vitamina C es una explicación razonable para esta
respuesta amenazante a la vida.
CONCLUSIONES: Este caso ilustra que la terapia complementaria puede
tener efectos serios y toxicidad potencialmente amenazante a la vida.
Este caso añade otra nota de precaución, específicamente, el potencial
para interacciones entre medicamentos complementarios distintos,
particularmente si no existe una tradición de uso concomitante.
OBJECTIF: L’amygdaline et le laetrile (forme synthétique d’amygdaline)
sont couramment utilisés comme compléments ou alternatives santé
dans le traitement du cancer. Nous décrivons ici un cas d’intoxication
sévère au cyanure suite à une ingestion unique d’amygdaline à des fins
RÉSUMÉ DU CAS: Une patiente cancéreuse de 68 ans s’est présentée aux
urgences peu après sa première prise du complément santé amygdaline
avec un score de Glasgow diminué, des convulsions, et une acidose
lactique sévère ayant nécessité intubation et ventilation. La patiente
prenait aussi 4800 mg par jour de vitamine C. Elle a rapidement répondu
au traitement par hydroxocobalamine. L’effet indésirable a été coté
comme probable sur l’échelle d’imputabilité de Naranjo.
DISCUSSION: La vitamine C est connue pour augmenter in vitro la
transformation d’amygdaline en cyanure et pour diminuer les réserves
corporelles en cystéine, qui intervient dans la détoxification du cyanure.
L’amygdaline a été utilisée pendant des décennies par les patients
cancéreux à la recherche de traitements alternatifs et il n’avait pas été
signalé de réactions sévères à cette dose. Une interaction avec la
vitamine C est une explication plausible de cette réaction mettant en jeu
le pronostic vital.
CONCLUSIONS: Ce cas illustre le fait que les compléments santé peuvent
présenter des toxicités sévères et mettre en jeu le pronostic vital. Ce cas
apporte un nouvel élément de précaution, à savoir le risque potentiel
d’interactions graves entre différents compléments santé, notamment
lorsqu’il n’existe pas d’expérience de leur co-utilisation.
Michel Le Duff