1. Introduction
Cancer, the leading cause of global death, accounted for approximately 19 million new cases and 10 million deaths in 2020. Fueled by population growth and aging, it is estimated that the number of cancer cases will increase to over 28 million by 2040 [
1].
Conventional tumor treatment includes surgical tumor resection, chemotherapy, and radiotherapy, either as single treatments or in combination. Despite significant therapeutic progress due to the recent approval of tyrosine kinase and immune checkpoint inhibitors, severe side effects and resistance development still prevent optimal drug efficacy. Dissatisfaction with conventional cancer protocols and the desire to activate the immune system in pursuit of a cure drives many cancer patients to seek complementary and alternative medicine (CAM) options. The term CAM has not been exactly defined but includes medical products and practices not included in standard medical care. Studies conducted in France and Poland have indicated that 85% of tumor patients integrate CAM into their treatment plans [
2,
3]. A regional survey in Sweden documented that more than 50% of cancer patients use CAM [
4], and an evaluation in Germany estimated that 50–90% of patients apply CAM [
5,
6,
7,
8].
Plant extracts or isolated plant-derived compounds are widely utilized CAM options. However, the popularity of herbal drugs is not met with accordant knowledge of their mode of action, and evidence-based clinical trials are sparse. Physicians and healers thus offer natural phytochemicals as potent remedies, although their benefits in terms of tumor suppression or immune augmentation remain unclear. Cancer patients themselves often seek advice from sources of unknown quality without critical evaluation [
9]. The discrepancy between the use of a phytodrug and knowledge about its mode of action is particularly evident for the cyanogenic diglucoside amygdalin (D-mandelonitrile-β-D-glucosido-6-β-D-glucoside), highly concentrated in fruit kernels from Rosaceae species such as peach and apricot. Amygdalin gained significant attention in the United States in the 1970s, with an estimated 70,000 annually treated cancer patients [
10].
The therapeutic use of amygdalin includes both oral and intravenous (i.v.) applications. Orally consumed amygdalin undergoes metabolism in the gastrointestinal tract, producing prunasin, mandelonitrile, glucose, benzaldehyde, and cyanide (HCN) through enzymatic β-glucosidase activity. HCN is subsequently detoxified through enzymatic conversion by rhodanase to thiocyanate (thiosulfate sulfurtransferase) [
11]. In contrast, i.v. administered amygdalin is excreted primarily unchanged, bypassing enzymatic degradation [
12].
The relevance of amygdalin as an anti-tumor drug is ambiguous. Under the presumption that tumor cells contain high amounts of β-glucosidase but reduced amounts of rhodanase compared to normal cells, proponents of amygdalin therapy claim that amygdalin selectively kills tumor cells by leading to an accumulation of HCN in these particular cells [
11]. Opponents of amygdalin therapy, however, warn that amygdalin is ineffective and HCN might systemically accumulate in the body with severe cyanide poisoning. Due to the potential risk of HCN intoxication, the sale of amygdalin for medical use has been forbidden in the United States and Europe (with few exceptions) [
13,
14]. Nevertheless, amygdalin is still administered with unknown prevalence as an anticancer drug.
Amygdalin has regained increasing attention over the last decade. However, although discussion about amygdalin’s clinical relevance has resurfaced, critical analysis is hindered by a lack of detail in medical practice. Aiming to provide updated insight into treatment concepts, a survey was distributed to physicians and healers who offer amygdalin treatment in Germany. Reasons for administration, dosing schedules, patient numbers, scientific training, efficacy assessment, incidence of toxicity, and degree of patient monitoring, including HCN detection, were surveyed.
4. Discussion
Nearly 20 cancer patients per practitioner were treated quarterly with amygdalin infusions. Extrapolating this figure to all 76 practitioners identified in our study, more than 1500 cancer patients receive amygdalin infusions quarterly. Given that new patients are treated each quarter, more than 6000 patients receive amygdalin infusions per year. Accounting for undetected prescribers, the actual number of cancer patients receiving intravenous amygdalin treatment could be substantially higher. A considerable number of patients could also be ingesting amygdalin tablets or apricot kernels without medical supervision. Considering the widespread use of amygdalin, little pertinent publication is available. Treatment through physicians and healers in Germany was investigated for the first time in the present study.
A cross-sectional study consisting of 166 Malaysian cancer patients using CAM indicated that oral amygdalin was “the most common dietary supplement” [
15]. A Polish survey conducted on internet forums and social networking sites found that among 177 CAM users, 50 cancer patients consumed amygdalin (28.3%) [
3]. The percentage of amygdalin users among inpatients and outpatients undergoing oncological treatment was calculated to be 5.3% [
16], while 10.8% of hospitalized Polish cancer patients who were aware of CAM declared amygdalin use [
17]. Information regarding amygdalin use in Germany is sparse. A survey on outpatient cancer patients has reported amygdalin use at 5.5% [
18].
Despite the lack of evidence supporting amygdalin efficacy in treating cancer and warnings regarding the risk of poisoning, its use by patients appears to be high [
19,
20]. The rationale behind the preference for amygdalin over other CAM options can only be speculated upon. While nearly all the study participants rated their communication with patients as excellent and believed that their patients also felt well-informed about amygdalin, it is possible that patients are influenced by practitioners convinced of amygdalin’s therapeutic potential. Facing advanced cancer, desperate and willing to try anything that may help, patients are susceptible to any promise of a cure [
21]. Goals and expectations must nevertheless be explained realistically, enabling patients to make informed, autonomous decisions about whether to use amygdalin or pursue alternative options.
The main reasons specified by the practitioners for administering amygdalin were symptom relief and delaying disease progression. Still, a number of them, particularly healers, indicated they administered amygdalin with the intent to cure. To date, there is no evidence to support the claim that amygdalin can cure cancer. The current survey does not address whether the belief in a cure was communicated to the patient. Without question, it is imperative to avoid making unrealistic promises to patients that could foster false hopes and unrealistic expectations. Striking a balance between achievability and unattainability is essential but also challenging, given that most available information on amygdalin is derived from antiquated studies. Undoubtedly, further research is warranted to provide a realistic assessment of amygdalin’s potential.
Therapeutic recommendations based on complementary and alternative medicine (CAM) may be influenced by economic interests. Indeed, three physicians mentioned the financial situation of patients as a limiting factor for initiating amygdalin infusions. Based on an internet search, a 3 g amygdalin vial for i.v. application costs less than 10 € [
22,
23], but in Germany, one pharmacy offers a 3 g vial for 30 € [
24]. Consequently, costs for one week’s treatment range from 150 € (3 g infusion/day) to 300 € (6 g infusion/day). Total treatment costs, including application and supervision, may, however, be higher.
Amygdalin was not always considered to be the treatment of choice. Some practitioners initiated amygdalin therapy solely due to patient requests. Other studies have identified insufficient knowledge of CAM and unsatisfactory dialogue with clinicians about CAM use as relevant factors contributing to patient demand [
25,
26]. Not requiring further consultation with their providers raises the question of how these patients obtain information about amygdalin. Clinically sound data with regard to amygdalin are scarce, with only two low-standard amygdalin trials having been conducted more than 40 years ago. These trials cannot serve as guidelines to evaluate amygdalin in the 21st century [
12]. Given the public interest in amygdalin and the uncertainties surrounding its efficacy, high-standard patient studies meeting randomized controlled trial criteria should be conducted. Presently, tumor patients tend to seek advice from family, friends, or other tumor patients, or they search the internet for information [
27,
28,
29].
Practitioners encounter similar challenges in regard to information about amygdalin. Initially, information is primarily obtained from colleagues and congresses, with medical congresses being perceived as less informative compared to naturopathic congresses. More than 30% of amygdalin providers reported that they obtained initial information about amygdalin from their patients. Therefore, amygdalin treatment concepts may be based on unverified anecdotal reports, mistakenly perceived as scientifically sound. The lack of evidence-based studies makes it difficult to distinguish between “serious” and “unserious” information. Despite growing interest, CAM remains under-represented in national and international cancer congresses. The healers and physicians in the present study advocate for open-mindedness among medical colleagues toward naturopathic treatment concepts. Indeed, efforts have been made in recent years to integrate CAM into cancer treatment services [
30,
31]. Still, a reputable forum for scientific exchange between medical and non-medical practitioners or between CAM users and non-CAM users has not been established.
In the present study, intravenous rather than orally administered amygdalin was considered more effective. However, it is unclear where this preference originated. Only one peer-reviewed manuscript has been published dealing with i.v. amygdalin to treat cancer patients [
32]. Therefore, it must be assumed that all information concerning i.v. amygdalin dosage has been taken from this report. Still, even the concentration used in this trial was not established in pilot tests but was rather determined from a “published compendium” of “some leading” practitioners treating with amygdalin [
32]. Respective information provided by Moertel et al. is also confusing. Although vials containing 3 g amygdalin for i.v. injections were ordered, and the treatment regimen pointed to an amygdalin concentration of 4.5 g/m
2 body surface area daily for three weeks. Presumably, two vials (6 g) of amygdalin were given per day. Contreras, a leading amygdalin pioneer, administered variable dosages ranging from 1 to 10 g amygdalin daily [
12,
33] but finally remarked that 6 g amygdalin i.v. daily was the most convenient method. There are also early reports on i.v. dosages of <1 g, 3, or 9 g amygdalin per day, applied by other amygdalin providers [
12,
34].
In the present investigation, the initial dose of 3 g amygdalin was most frequently applied with an increase to a maximum of 9 g/day in the majority of cases. This is within the range of the concentrations applied by the amygdalin pioneers. However, over 60% of providers treated their patients with >9 g/day amygdalin, a practice not supported by early reports. Dosage was not tied to the body surface area as practiced by Moertel et al. [
12]. Rather, amygdalin was applied in 3 g units, i.e., 3 g or a multiple of 3 g. Nearly half of the amygdalin appliers based their dosage decisions on their “own experience”. Elevating the amygdalin dose was particularly common in cases of limited response or worsened condition. This approach carries significant risk, as a loss of response to treatment may indicate either a lack of anti-tumor effect or the development of resistance. Elevating amygdalin dosage under these circumstances could further exacerbate the patient’s precarious condition.
Amygdalin was administered at regular intervals in most cases, which aligns with the protocol introduced by Moertel et al., which involves intravenous injections over three weeks (on consecutive days or weekdays only). Moertel et al. additionally pointed to the published recommendations of Ernest Krebs, Jr., who developed the injectable form of amygdalin and stated that intravenous treatment should be administered over periods ranging from 10 to 31 days [
32].
In current clinical practice, monitoring serum tumor markers is common for assessing therapeutic response. According to the surveyed practitioners, laboratory data was considered the most relevant factor for evaluating treatment success. Still, the term “laboratory data” was often unspecified, leaving room for non-established tests to be used. Five amygdalin providers assessed therapeutic response by the EDIM test (Epitope Detection in Monocytes). This test quantifies the expression level of the enzyme transketolase-like 1 (TKTL1) in monocytes and is popular among alternative practitioners but plays no role in conventional medicine. A recent study on patients undergoing curative radical prostatectomy demonstrated no correlation between serum TKTL1 and serum PSA, Gleason score, tumor stage, or further clinical and pathologic parameters [
35]. Hence, TKTL1 should not be considered a specific biomarker, as misinterpretation could lead to erroneous treatment decisions. It is essential to monitor patient response rigorously, using well-established guideline-based tests, especially given amygdalin’s status as a non-standard therapy with unknown efficacy. Encouragingly, 65% of the surveyed practitioners monitored therapeutic success through clinical examination and/or medical imaging, a practice worthy of commendation.
Good communication between amygdalin providers and other healthcare providers is absent. Many physicians have limited knowledge about CAM, hampering dialog between naturopaths and physicians. This disconnect extends to the perceived irrelevance of physicians' letters in guiding therapeutic decisions, and open-mindedness is called for on both sides. Acknowledging that differing perspectives on complementary treatment methods may exist between CAM providers and healthcare providers who do not utilize CAM could optimize patient outcomes.
Questions concerning amygdalin’s value as an anti-cancer drug have been raised in regard to the risk of HCN poisoning. In this survey, severe adverse events were not reported. A few cases of dizziness and nausea were observed, but these were independent of amygdalin concentration or application time. This aligns with findings from the Moertel study, demonstrating no clinical or laboratory evidence of toxicity when amygdalin was given intravenously at 6 g/day [
11]. Another study evaluating cyanide levels after chronic oral amygdalin intake and subsequent intravenous amygdalin administration also found no signs of HCN intoxication, such as nausea, dizziness, or loss of consciousness [
36]. Similarly, no serious adverse events have been recorded when healthy subjects have repeatedly been given intravenous amygdalin infusions [
37].
It cannot be excluded that the (moderate) negative effects recorded in the present investigation were caused by conventional therapy. However, this seems unlikely since patients were questioned about negative side effects observed during the actual amygdalin infusion. One participant noted nausea that disappeared after 1 h. Another reported fatigue that disappeared after 4 h, and one patient complained of a mild headache that disappeared when the infusion was slowed. While amygdalin infusion appears to be safe for treating cancer patients, careful monitoring during and after treatment is important. Fortunately, amygdalin infusions are only administered in the healer’s or physician’s practice, ensuring proper oversight.
A significant concern arises with oral amygdalin consumption at home, especially considering the limited follow-up reported by only 13% of the surveyed practitioners. A proper maintenance dosage typically involves ingesting 1–3 tablets containing 0.5–1.5 mg of amygdalin per day [
32]. In a small pilot study, no clinical or laboratory evidence of toxic reaction was observed in patients taking 0.5 g amygdalin orally three times daily [
11]. However, headaches, dizziness, nausea, and vomiting have been observed in a few patients following the consumption of 3 tablets (1.5 g amygdalin) per day [
32]. Another study reported no HCN-related side effects with daily doses of 0.5–2 g for 2–43 weeks [
38]. Despite these findings, several cases of severe toxicity and even death after oral amygdalin consumption have been documented, which, however, were related to substantial overdosing and/or additional chewing of a large quantity of apricot kernels [
12]. The risk of cyanide poisoning from uncontrolled amygdalin consumption at home should, therefore, not be underestimated. Particularly the argument that “the more, the better” may drive patients to increase their dosage arbitrarily without informing their healthcare provider.
The reason for the lack of compliance control can only be speculated upon. It is not clear whether amygdalin providers are aware of the risk associated with amygdalin. Possibly, their daily workload does not allow for a careful follow-up. A low-interest level might also be a reason why patients were not controlled at home. In fact, this survey documents a lack of communication between the amygdalin providers and other healthcare providers, along with a limited interest in patient-reported outcomes and physicians’ letters. Due to the risk of overdosing, frequent monitoring in the form of telephone calls or messaging apps [
39,
40] after patients leave the practice should be mandatory.
Ames et al. and Moertel et al. [
11,
41] reported that amygdalin is rapidly cleared from the blood and excreted largely unchanged in the urine when administered i.v. Nearly all practitioners in the present survey deemed it unnecessary to determine blood HCN levels since amygdalin is not metabolized to HCN when given i.v. In vivo studies conducted on rats and dogs point to an amygdalin excretion rate of approximately 80% [
42], which has been verified in healthy men [
37]. The lack of amygdalin metabolization to HCN might explain why no HCN-related side effects have been observed in cancer patients following i.v. amygdalin treatment. However, this opens the question about the anti-tumor mechanism of amygdalin, assumed to be due to HCN specifically accumulating in cancer cells. All surveyed practitioners were convinced that i.v. amygdalin application was the most effective treatment method. However, under the assumption that HCN is relevant to destroying cancer cells, oral consumption of amygdalin (producing high amounts of HCN) might be superior to i.v. treatment. Only a minority of amygdalin providers monitored their patients consuming tablets orally at home, making it difficult to draw definitive conclusions. Studies by Mani et al. detected an increase in the HCN blood level following amygdalin injection [
36], indicating that at least some degree of metabolization may occur independently of gut flora activity. However, this remains speculative. The discrepancy between the assumed mode of action of amygdalin and the lack of HCN synthesis after i.v. application calls for further research. In vitro studies have shown that amygdalin induces apoptosis, suppresses proliferation, and inhibits the metastatic spread of cancer cells. Recent experiments by Zhang et al. on rats have proposed that amygdalin is deglycosylated to prunasin, its active metabolite [
43]. Other approaches point to the protective effects of amygdalin on epithelial–mesenchymal transformation in mice [
44,
45]. There is also evidence that amygdalin inhibits prostate [
46], lung [
47], and liver [
48] cancer growth in vivo. These reports open new avenues for understanding amygdalin’s mechanism of action and highlight the urgency of conducting animal and clinical studies to validate these findings.
The physicians and healers participating in this survey recognized the need for more effort leading to a realistic assessment of amygdalin’s value. Enrolling in clinical trials on CAM was one of the most requested actions. It is, therefore, disappointing that the interest in actively participating in future studies was moderate, with only one-third of the surveyed individuals agreeing to provide data for scientific analysis. Whether these non-interested providers were actually overloaded with work, whether they did not want to make their (anonymously submitted) data public, or whether they feared a negative impact on the future use of amygdalin remains unclear. Assessing the effectiveness of amygdalin for cancer care remains limited as long as relevant study data are unavailable. Hence, amygdalin providers should become more engaged in scientific research to open fruitful discussions based on evidence rather than speculation. While it may be unrealistic to expect a randomized controlled trial, single case reports may also provide valuable information.
Limitations of this study should be considered. Most of the patients taking amygdalin also received conventional therapy. Therefore, effects thought to be due to amygdalin (e.g.,
Table 17) could have been due to conventional treatment. Some responses (e.g.,
Table 8) particularly reflect the personal opinion of the practitioner and might be unduly positive. A new study is therefore aimed at attaining information from the patient’s point of view. It will include not only the patient’s assessment of amygdalin’s anti-tumor potential, assessment of counseling, and overall satisfaction but also long-term observation and patient-reported outcome.