IngredientsAmygdalin (d-Mandelonitrile 6-O-β-d-glucosido-β-d-glucoside) is a naturally occurring disaccharide, a source of HCN, highly concentrated in fruit kernels from Rosaceae species, for example, in bitter almonds, apricot, and peach. 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.
Amygdalin is a benzaldehyde, hydrocyanic acid, and glucose-containing aromatic aminoglycoside with the chemical formula C20H27NO11. The chemical name for amygdalin is (R)-α-[(6-O-β-D-glucopyranosyl-β-D-glucopyranosyl-oxy)]-(phenyl)acetonitrile, also known as d-(−)-mandelonitrile-β-d-gentiobioside. It is a colorless substance with a molecular mass of 457.4 g/mol, a melting point of 213 °C, and the CAS number 29883-15-6. It is insoluble in chloroform, a non-polar solvent; however, it is moderately soluble in water and highly soluble in ethanol.
Amygdalin is composed of two molecules of glucose, benzaldehyde, and hydrogen cyanide, and can exist in the form of two R and S epimers. R-amygdalin is natural amygdalin, and S-amygdalin is called neoamygdalin. Amygdalin is a cyanogenic glycoside derived from the aromatic amino acid phenylalanine.
Amygdalin (from Ancient Greek: ἀμυγδαλή amygdalē, "almond") is a naturally occurring chemical compound found in many plants, such as the seeds (kernels, pips, or stones) of apricots, bitter almonds, apples, peaches, cherries, and plums, and in the roots of manioc.
Amygdalin is contained in Rosaceae plants and stone fruit kernels, such as almonds, apricot (14 g/kg), red cherry (3.9 g/kg), black cherry (2.7 g/kg), peach (6.8 g/kg), and plum (4–17.5 g/kg depending on variety), and also in the seeds of the apple (3 g/kg). In one study, bitter almond amygdalin concentrations ranged from 33 to 54 g/kg depending on variety; semi-bitter varieties averaged 1 g/kg and sweet varieties averaged 0.063 g/kg, with significant variability based on variety and growing region.
A semi-synthetic form of amygdalin called laetrile — also marketed as vitamin B17, although not a vitamin — is produced from hydrolysis of amygdalin obtained from apricot kernels. Amygdalin occurs in many plants, notably in seeds of fruits in the Rosaceae family such as bitter almonds, apricots, and plums. Laetrile is a derivative of amygdalin formed by the hydrolytic removal of one glycoside group from the parent compound.
In the 1950s, an intravenous form of amygdalin was patented and named laetrile, which is an acronym from "laevorotatory" and "mandelonitrile." The form patented in the USA, albeit not approved, is a semi-synthetic compound consisting of D-glucuronic acid and mandelonitrile, while laetrile made in Mexico is extracted from crushed apricot kernels and consists of amygdalin. Laetrile is prepared for oral as well as for intravenous or intramuscular application.
Laetrile is given by mouth (orally) as a pill. It can also be given by injection into a vein (IV) or muscle (intramuscular). The literature is a bit confusing because the names "amygdalin" and "laetrile" are sometimes conflated. Both molecules are also erroneously termed vitamin B17.
Bitter almonds have been used since ancient times to treat fevers and headache (via their purging activity) and as a diuretic. Bitter almonds containing amygdalin are used in Traditional Chinese Medicine to remove "blood stasis" and to treat abscesses.
Amygdalin has been used as a traditional drug because of its wide range of medicinal benefits, including curing or preventing cancer, relieving fever, suppressing cough, and quenching thirst.
The chemical properties of amygdalin from bitter almond seeds were first described by the German chemists Liebig and Wöhler in 1837, after having been isolated seven years earlier by the French chemists Pierre-Jean Robiquet and A. F. Boutron-Charlard. Amygdalin was first isolated from bitter almonds (Prunus dulcis) in the 1830s by Robiquet and Boutron-Charlard. Early investigations by chemists like Liebig and Wöhler identified amygdalin as non-toxic after animal experimentation.
Amygdalin was isolated by French chemists in 1830 and it was first used as a treatment for cancer in Russia in 1845. In 1845, it was tested as a potential cancer treatment in Russia but was quickly abandoned due to its high toxicity and poor efficacy. Germany rejected this cancer treatment in 1892.
In the United States, interest in amygdalin surged in the 1920s, although initial oral formulations were deemed too toxic for use. The 1950s saw the development of a semi-synthetic injectable form of amygdalin known as laetrile, patented by Ernst T. Krebs. Amygdalin was first used to treat cancer more than a century ago in Russia and later in the United States. A purified form sold as laetrile has been a popular alternative cancer therapy since the 1960s.
Some claimed amygdalin to be a vitamin (B17) and that deficiencies could cause cancer, but this is not substantiated by scientific evidence.
After oral administration, amygdalin is broken down by amygdalin lyase into prunasin and glucose, both of which are non-toxic. Prunasin lyase catalyzes the hydrolysis of prunasin, resulting in glucose and mandelonitrile. Then, OH-nitrile lyase breaks down the mandelonitrile into hydrogen cyanide and benzaldehyde. Beta-glucosidase stored in compartments of plant cells is also present in the human small intestine and degrades amygdalin into prunasin, mandelonitrile, glucose, benzaldehyde, and hydrogen cyanide.
β-Glucosidase is a key enzyme for cyanide release from amygdalin, and lower expression of rhodanese is observed in tumor tissue compared to normal tissue. Excessive cyanide ion can bind to Fe3+ in Complex IV of the mitochondrial electron transport chain (cytochrome c oxidase) and inactivate the enzyme, leading to interruption of intracellular respiration.
Following consumption by animals including humans, hydrogen cyanide may also be generated by the action of enzymes from the gut microflora on ingested intact cyanogenic glycosides.
The basic anticancer molecular mechanisms of amygdalin have mainly been ascribed to cell cycle inhibition, apoptosis induction, cytotoxic effect stimulation, and immune function regulation within the human body.
In vitro experiments have shown induction of apoptosis by amygdalin as a result of increased expression of Bax protein and caspase-3 and reduced expression of anti-apoptotic Bcl-2 protein. Amygdalin activates p38MAPK, which affects death stimuli: activates Bax apoptotic proteins, and inhibits Bcl-2 anti-apoptotic proteins. Apoptosis-related proteins induce mitochondrial outer membrane permeabilization (MOMP), a decisive event in the process of cytochrome c release. Activation of the release of cytochrome c as a mitochondrial response to pro-apoptotic stimuli via the mitochondrial or intrinsic apoptotic pathway ultimately leads to activation of caspases including caspase-3, which induces apoptosis.
Amygdalin treatment increased expression of Bax, decreased expression of Bcl-2, and induced caspase-3 activation in human DU145 and LNCaP prostate cancer cells; it induced apoptosis of HeLa cervical cancer cells mediated by the endogenous mitochondrial pathway and reduced adhesion and migration of UMUC-3 and RT112 bladder cancer cells through activation of focal adhesion kinase (FAK) and modulation of β1 integrin. Amygdalin has also the ability to inhibit anti-apoptotic expression of genes including Survivin and XIAP.
Amygdalin has also been shown to inhibit the adhesion of breast cancer cells, lung cancer cells, and bladder cancer cells by decreased expression of integrins, reduction of catenin levels, and inhibition of the Akt-mTOR pathway, which may consequently lead to inhibition of metastasis.
Amygdalin has shown anti-inflammatory potential in inhibiting IL-1α, IL-1β, IL-6, IL-9, TNF-α, and MCP-1.
Amygdalin is composed of two molecules of glucose, one of benzaldehyde, which induces an analgesic action, and one of hydrocyanic acid, which is an anti-neoplastic compound.
Several studies have demonstrated a wide range of biological properties for amygdalin, suggesting that it may exert a preventive or even a co-treatment impact on cervical, breast, prostate, lung, and bladder cancers, which may mainly be ascribed to the inhibition of cancer cell proliferation.
Chang et al. found that amygdalin up-regulated Bax, down-regulated Bcl-2, and increased the activity of caspase-3 in DU145 and LNCaP prostate cancer cells. Chen et al. found that amygdalin could promote apoptosis by increasing caspase-3 activity in DAPI-stained HeLa cells, and Bcl-2 was down-regulated while Bax was up-regulated in amygdalin-treated HeLa cells, suggesting that an intrinsic pathway may be involved in apoptosis.
Lee et al. determined the expression levels of apoptosis-related proteins in breast cancer cells treated with amygdalin at various concentrations and found that amygdalin increased the expression of pro-apoptotic protein Bax and decreased that of anti-apoptotic Bcl-2 and pro-Caspase-3. At the same time, PARP cleavage was observed in breast cancer cells treated with amygdalin.
Amygdalin may inhibit growth and proliferation in bladder cancer cell lines by decreasing cell cycle regulatory proteins cdk2 and cyclin A. It also induces growth-regulating protein follistatin expression in human hepatocarcinoma cells.
All of the above constitute in vitro (cell-line) evidence only. Well-planned clinical trials are still needed to be conducted to prove effectiveness of this substance in vivo and to obtain approval for human use.
In 1978, the National Cancer Institute (NCI) requested case reports from practitioners who believed that their patients had benefited from laetrile treatment. Ninety-three cases were submitted, and 67 were considered evaluable for response. An expert panel concluded that two of the 67 patients had complete responses and that four of the others had partial responses while using laetrile. On the basis of these six responses, the NCI agreed to sponsor Phase I and Phase II clinical trials.
The Phase I study was designed to test the doses, routes of administration, and the schedule judged representative of those used by laetrile practitioners. The study involved six cancer patients. The investigators found that IV and oral amygdalin showed minimal toxicity under the conditions evaluated; however, two patients who ate raw almonds while undergoing oral treatment developed symptoms of cyanide poisoning.
The Phase II trial conducted by the NCI evaluated 175 patients with cancer, primarily of the lung, breast, and colorectal regions. Patients received 21 daily intravenous injections of 4.5 g/m2 followed by oral maintenance therapy at 0.5 g three times daily. Patients also followed a "metabolic therapy" program that consisted of a diet with enzyme and vitamin supplements. The only tumor response reported was a single partial response that lasted for 10 weeks.
In about half of the patients, cancer had grown by the end of the treatment. Cancer had grown in all patients 7 months after treatment ended. Patients reported improved symptoms, such as the ability to work or do other activities. These improvements did not last after treatment ended.
A Cochrane systematic review found no evidence from RCTs or quasi-RCTs for the use of laetrile or amygdalin in cancer treatment. The review concluded that "the evidence, beyond reasonable doubt, is that it [laetrile] doesn't benefit patients with advanced cancer, and there is no reason to believe that it would be any more effective in the earlier stages of the disease."
A systematic review identified 36 reports meeting inclusion criteria. No controlled clinical trials were found. Three articles were non-consecutive case series, two were consecutive case series, six were best-case series, and 25 were case reports. None of these publications proved the effectiveness of laetrile. Therefore, the claim that laetrile has beneficial effects for cancer patients is not supported by sound clinical data.
Amygdalin is a medically interesting but controversial compound as it has anticancer activity on one hand and can be toxic via enzymatic degradation and production of hydrogen cyanide on the other. Despite numerous contributions on cancer cell lines, the clinical evidence for the anticancer activity of amygdalin is not fully confirmed.
Evidence strength: In vitro evidence is consistent but limited to cell lines. Animal data are limited. Human clinical evidence, reviewed by the Cochrane Collaboration and the NCI, fails to demonstrate anticancer efficacy. No randomized controlled trials exist.
In vitro studies of the biological activity of amygdalin and its compounds showed positive effects related to their antifibrotic, anti-inflammatory, antiasthmatic, and immunoregulatory processes. These are primarily preclinical findings. Antioxidant, anti-tumor, anti-fibrotic, anti-atherosclerosis, anti-inflammatory, immunomodulatory, and analgesic characteristics, as well as the ability to improve digestive and reproductive systems, neurodegeneration, and cardiac hypertrophy, are reported biological properties of amygdalin.
Evidence strength: Mostly in vitro and animal studies; no robust human clinical trials on anti-inflammatory outcomes.
Treatment of cultured renal interstitial fibroblasts with amygdalin inhibited their proliferation and the production of transforming growth factor (TGF)-β1. In a rat model of obstructive nephropathy, following ureteral obstruction, the administration of amygdalin eliminated extracellular matrix accumulation and alleviated renal injury on the 21st day. Collectively, amygdalin attenuated kidney fibroblast (KFB) activation and rat renal interstitial fibrosis. These results indicate that amygdalin is a potent anti-fibrotic agent that may have therapeutic potential for patients with fibrotic kidney diseases.
Evidence strength: In vitro and animal (rodent) studies only; no human clinical trials on renal fibrosis outcomes.
Amygdalin is also noted as being used to manage asthma, improve the immune system, induce apoptosis in human renal fibroblasts, and inhibit hyperglycemia. Preclinical data suggest selective inhibition of type 2 helper T cell responses relevant to asthma; however, these findings are not confirmed in human trials.
Evidence strength: Preliminary preclinical; no human clinical trial evidence available.
Amygdalin has been reported to mediate relieved atherosclerosis in apolipoprotein E-deficient mice through the induction of regulatory T cells. This is animal data only.
Evidence strength: Animal studies only; no human data.
Laetrile/amygdalin is given by mouth (orally) as a pill. It can also be given by injection into a vein (IV) or muscle (intramuscular).
In the NCI Phase I trial, under intravenous administration (4.5 g/m2/day), amygdalin did not produce any toxicity (no cyanide in blood). Greatest concern was with the oral route of administration (3 × 0.5 g/day), at which there was definite elevation of cyanide in blood and peak levels were different in every patient.
In the NCI Phase II study, patients received 21 daily intravenous injections of 4.5 g/m2 followed by oral maintenance therapy at 0.5 g three times daily, and patients also followed a "metabolic therapy" program consisting of a diet with enzyme and vitamin supplements.
In an earlier observational study, patients with progressive disease were given amygdalin daily, 0.5–2 g orally, for 2–43 weeks. One patient experienced improvement by reduced tumor-derived stenosis over 9 weeks and two patients reported well-being improvements. In the remaining 22 patients, no improvement was observed.
In cell-line studies, the expression of Bcl-2 mRNA and protein might be suppressed by amygdalin (0.1–10 mg/mL) in DU145 and LNCaP prostate cancer cells. In addition to increasing caspase-3 enzyme activity, it triggered apoptosis with typical morphological features. When added to Hs578T breast cancer cells, amygdalin (10–40 mg/mL) drastically reduced Bcl-2 expression while increasing Bax expression and triggering the cleavage of caspase-3 and poly ADP-ribose polymerase.
Regarding minimum lethal dose, the minimum lethal dose of amygdalin for an adult is reported as 50 mg, or 0.5–3.5 mg/kg of body mass.
A key route-of-administration finding is that animal trials using 500 mg/kg of amygdalin administered intravenously revealed no fatalities, while the same amount administered intragastrically resulted in 80% mortality.
Upon ingestion, amygdalin and laetrile are both hydrolyzed by intestinal beta-glucosidase, releasing a cyanide anion. Hydrogen cyanide production after oral ingestion of amygdalin (laetrile) can cause fatal cyanide poisoning, particularly in high oral doses or when co-ingested with fruit kernels, almonds, or high-dose vitamin C.
HCN impedes cell respiration and also interacts with cytochrome oxidase. The cyanide ion (CN−) is formed during the metabolism and absorption of hydrocyanic acid, inhibiting the body's capacity to use oxygen by interfering with the respiratory electron transfer mechanism. Amygdalin is harmful because it causes cells to undergo hypoxia and lactic acidosis.
Contaminated and adulterated products have been found in both injectable and oral forms. Case reports of dermatitis and cyanide toxicity include nausea, vomiting, headache, dizziness, altered alertness, cyanosis, hypotension, eyelid droop, neuropathies, coma, and death with oral intake.
A documented case report: 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 was also ingesting 4800 mg of vitamin C per day. She responded rapidly to hydroxocobalamin treatment.
Another documented case: A patient taking three amygdalin tablets (500 mg each) developed altered mental status, diaphoresis, tachycardia, vomiting, dizziness, and crampy abdominal pain approximately 45 minutes after the first dose. In the emergency department, the patient was confused with a GCS of 10.
In a comparative toxicokinetics study of amygdalin performed in normal and pseudo germ-free rats, the efficiency of cyanide release was significantly higher in the normal group when given a single oral dose of 440 mg/kg (50% median lethal dose). Thiocyanate, the detoxification metabolite, was first detected in feces, caecum, and intestinal microbiota incubation enzymatic systems. The results suggest intestinal microbiota is involved in bidirectional regulation of toxicity and detoxification of amygdalin.
Species related to cyanogenesis of amygdalin were identified as Bifidobacterium pseudolongum, Marvinbryantia formatexigens, and Bacteroides fragilis. The sulfurtransferase superfamily, such as rhodanese, considered the main detoxification enzymes for cyanide, are largely found in Coriobacteriaceae bacterium, Butyricicoccus porcorum, and Akkermansia muciniphila.
Factors like probiotic or prebiotic consumption, other complementary and alternative medicine (CAM) therapies, obesity, diet, and age, which alter gut consortium, are responsible for the varying conditions under which toxicity occurs.
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. Cyanide poisonings have been documented following ingestion of amygdalin with concurrent high-dose vitamin C or apricot kernels.
Studies revealed that amygdalin's toxicity was caused by its poisonous decomposition products of benzaldehyde and hydrogen cyanide after oral ingestion, and the toxicity of the intravenous administration route was far less than the oral route. Amygdalin was initially supposed to be a safe drug for cancer treatment, as it was considered to be hydrolyzed only in cancer cells, releasing toxic hydrogen cyanide. Unfortunately, current studies have shown that HCN is also released in normal cells, therefore it may not be safe for the human organism.
An analysis conducted by the National Cancer Institute (NCI) to assess the purity of both oral and injectable amygdalin products indicated that they were substandard by US criteria for pharmaceutical products. Other studies also showed the presence of contaminants in both injectable and oral supplements of laetrile.
Peripheral neuropathy has been reported following consumption of amygdalin by a patient with vitamin B12 deficiency.
The National Cancer Institute sponsored Phase I–II clinical trials but found no evidence to support the clinical benefits of amygdalin in cancer treatment. Furthermore, amygdalin was associated with cyanide poisoning, especially from oral ingestion. As a result, the Food and Drug Administration (FDA) banned the sale of amygdalin as a medicinal product. Laetrile has been banned by the FDA since the 1980s and is not authorized for sale as a medicinal product in the European Community. Nevertheless, it continues to be manufactured and administered as an anti-cancer therapy.
The high risk of developing serious adverse effects from cyanide poisoning after laetrile or amygdalin, especially after oral ingestion, is considerable.
Health conditions that Amygdalin may help support.
Body systems that Amygdalin may help support.
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