Introduction
Throughout human evolutionary history, our interaction with both primate ancestors and domesticated animals has resulted in the acquisition of approximately 300 species of parasitic worms (Król et al., 2019) and over 70 species of protozoa (Cox, 2002). Ancient fecal samples have yielded evidence of nearly all known parasites specific to humans (Araújo et al., 2003). A Parasite is an organism that lives in or on another species, known as its host, deriving nutrients at the host’s expense, thus causing what is commonly referred to as a parasitic infection (Forman & Maryanti, 2021). Parasitology traditionally limits its focus to protozoa (Imam, 2009). T, helminths (McVeigh, 2020), arthropods (Di Giovanni et al., 2021), and their vector species, although it is entirely proper from a biological standpoint to classify bacteria, fungi, and viruses as parasites (Bogitsh, Carter, & Oeltmann, 2013).
Human parasitic infections represent a significant public health burden worldwide, particularly in tropical and subtropical regions (Ung et al., 2021; Bogitsh, Carter, & Oeltmann, 2013, p. 7). These infections are caused by various protozoa, helminths, and ectoparasites, leading to a range of clinical manifestations from mild discomfort to severe morbidity and mortality (Cox, 2002). Some of the most common parasitic diseases include malaria, schistosomiasis, lymphatic filariasis, soil transmitted helminthiasis, and leishmaniasis (Ung et al. 2021).
Figure 1. Global Parasitic Disease Epidemiology. Adapted from Nag & Kalita, (2022)
Common Parasitic Diseases: Clinical Overview
Malaria, caused by Plasmodium parasites and transmitted through the bite of infected mosquitoes, remains a major cause of morbidity and mortality worldwide, particularly in sub-Saharan Africa. (Bogitsh, Carter, & Oeltmann, 2013, p. 116). Despite significant progress in control efforts, including the distribution of insecticide-treated bed nets and antimalarial drugs, challenges such as insecticide resistance and limited access to healthcare continue to hinder eradication efforts (Ung et al. 2021).
Schistosomiasis, transmitted through contact with contaminated water inhabited by freshwater snails carrying Schistosoma parasites, affects over 200 million people globally, primarily in tropical and subtropical regions (Mutuku, 2020). The disease can lead to chronic complications such as liver and spleen enlargement, bladder cancer, and kidney damage, contributing to the cycle of poverty and economic instability in affected communities (Ung et al. 2021).
Lymphatic filariasis, caused by filarial worms transmitted through the bites of infected mosquitoes, affects over 120 million people worldwide, causing severe disability and disfigurement. The disease can lead to lymphedema, elephantiasis, and hydrocele, significantly impacting the quality of life of affected individuals and imposing a considerable economic burden on endemic countries (Ung et al. 2021).
Soil-transmitted helminthiasis, including infections with roundworms, whipworms, and hookworms, affects over 1.5 billion people globally, particularly in areas with poor sanitation and hygiene practices. These parasites thrive in warm and humid environments and can lead to malnutrition, anemia, and impaired cognitive development, particularly in children (Ung et al. 2021).
Leishmaniasis, caused by Leishmania parasites transmitted through the bite of infected sandflies, manifests in various clinical forms ranging from cutaneous lesions to visceral involvement, depending on the species of parasite and host immune response. The disease affects millions of people worldwide, with an estimated 350 million people at risk of infection in endemic regions (Ung et al. 2021).
Conventional treatment approaches often rely on antiparasitic drugs, which may be associated with limitations such as drug resistance (Pink et al., 2005), toxicity (Rosenblatt, 1992), and cost (Shahriar, & Alpern, 2020). Classic antiparasitic drugs, including chloroquine for malaria, metronidazole for amoebiasis, and praziquantel for helminthic infections, are extensively discussed in the review by Campbell and Soman-Faulkner (2023).
Table 1. Antiparasitic Drugs and Their Targeted Parasites (Campbell and Soman-Faulkner, 2023)
The World Health Organization (WHO) recognizes 36 antiparasitic drugs as essential, underscoring their critical role in global health initiatives (Arete-Zoe, 2017). Synthetic drugs are commonly used to treat parasitic diseases, but exploring plant-based compounds presents an intriguing avenue for potential advancements in treatment.
A review by Ranasinghe et al. (2023) evaluated 507 plant species, primarily from the Fabaceae, Asteraceae, Combretaceae, and Lamiaceae families, for their antiparasitic effects against gastrointestinal parasites, with a focus on organisms such as Entamoeba histolytica and Giardia duodenalis; ninety-one plant species and thirty-four compounds were identified as demonstrating significant in vitro efficacy against parasites.
Figure 2. A One Health approach to the global control of parasitic diseases, emphasizing the interconnectedness of human, environmental, and animal health. Adapted from Ung et al. (2021).
The One Health paradigm is an approach to addressing complex health challenges that recognizes the interconnectedness of human health, animal health, and environmental health. It emphasizes the interdependence of humans, animals, and ecosystems, understanding that the health of one affects the others. In the context of parasitic diseases, the One Health approach recognizes that many of these diseases are zoonotic, meaning they can be transmitted between animals and humans (Ung et al., 2021).
Nutrition significantly influences susceptibility to all parasitic infections (Coop, & Kyriazakis, 1999). Malnutrition, especially protein deficiency, heightens vulnerability, exacerbating conditions like hookworm infection, leading to anemia, weight loss, abdominal swelling, and mental fatigue (Bogitsh, Carter, & Oeltmann, 2013, p. 10).
Poor nutrition not only increases susceptibility to parasitic infections but also can be both a consequence and exacerbating factor of infection-induced malnutrition. Onchocerciasis, the second leading infectious cause of blindness globally, affects 20 million people, mainly in tropical Africa, with 120 million at risk. Caused by Onchocerca volvulus, it leads to “river blindness” and severe dermatitis, resembling vitamin A deficiency symptoms , suggesting a possible competition for or interference with vitamin A metabolism in the host (Bogitsh, Carter, & Oeltmann, 2013, p. 337- 338). De Gier et al. (2014) analyzed 37 studies on Helminth infections and micronutrients in school-age children and found that helminth infections correlate with decreased serum retinol but not ferritin levels in children, concluding that further research on other micronutrients is needed.
Orthomolecular Medicine and its Potential Role in Addressing Parasitic Infections
Orthomolecular medicine, as defined by Pauling in 1968, focuses on restoring and maintaining health through the administration of substances naturally present in the body. The aging process, often accelerated by factors like free radical exposure (Migliore & Coppedè, 2009), inflammation (Bektas, et al, 2018), and toxic exposures (Dutta, et al., 2023), can be slowed or reversed through orthomolecular therapy, alongside addressing health issues (Carter, 2019).
Orthomolecular medicine can potentially contribute to the One Health approach by emphasizing optimal nutrition and natural substances to boost immune function, support host resistance, and reduce parasite burden in both humans and animals, thus complementing efforts to control parasitic diseases while promoting overall health and well-being. Global aging poses a multifaceted challenge within the One Health paradigm; Aging, influenced by a multitude of interconnected factors such as bio-genetics, environment, and socioeconomic forces, not only manifests internal vulnerabilities like frailty and comorbidities but also external challenges such as social isolation and financial strain, collectively rendering the elderly population more susceptible to infections, including parasitic infections (Forman & Maryanti, 2021).
Scientific studies increasingly support the therapeutic and preventive benefits of high doses of nutrients. Vitamins C and E, beta-carotene, B-complex vitamins, and coenzyme Q10 have demonstrated positive effects on health and longevity at doses exceeding the Recommended Dietary Allowance (RDA). Although mineral requirements, such as magnesium, zinc, and chromium, are closer to the RDA, supplements beyond dietary levels may still be necessary for disease prevention, treatment, and slowing the aging process (Carter, 2019).
Orthomolecular medicine offers a potential alternative therapy for parasitic infections. By restoring health through the administration of natural substances present in the body (Hemat, 2004), orthomolecular medicine addresses underlying health issues while slowing the aging process (Carter, 2019). High-dose nutrient supplementation, a cornerstone of orthomolecular therapy, (Cathcart, Cott, & Foster 2014) has shown promising therapeutic and preventive benefits in various health conditions (Carter, 2019). However, its efficacy in treating parasitic infections at orthomolecular doses remains largely unexplored.
The immune response to parasites involves a complex interplay of defense mechanisms. Nitric oxide (NO) plays a crucial role by targeting cysteine proteases essential for parasite life cycles and host-parasite interactions (Ascenzi et al., 2003). Histones, known for DNA regulation, also act as key mediators of host defense, triggering inflammatory responses and directly combating parasites (Hoeksema et al., 2016).
Additionally, a robust IFN-γ response in humans indicates effective pro-inflammatory action against parasites (Artavanis Tsakonas et al., 2003). Despite variations among parasite groups, common immune reactions are activated upon infection, involving pattern recognition, inflammatory signaling, effector molecule expression, antigen presentation, and establishment of adaptive immune responses, contributing to infection control (Buchmann, 2022). This orchestrated immune response highlights the host’s intricate mechanisms to combat parasitic challenges. Huemer (2006), while exploring the orthomolecular ramifications of chronic renal disease, highlights the importance of mega doses of vitamins B6, B12, folate, and trimethyl glycine (betaine), in increasing nitric oxide levels by inhibiting homocysteine.
According to Mikirova (2020), continuous ascorbate infusions may stimulate histone function, potentially influencing gene expression. Short-term supplementation with 750 mg of vitamin E leads to increased production of the T helper 1 cytokine IFN-gamma (Malmberg et al., 2002; Saul, 2003).
The effectiveness of Vitamin C to enhance the innate immune response is well established (Hoang et al, 2020), and high dose vitamin C showed a non-significant trend towards increased cell-mediated immune responses in healthy elderly individuals (Goodwin et al, 1983).
Recent clinical trials indicate that vitamin A supplementation reduces morbidity and mortality in various infectious diseases, while studies in animal models and cell lines highlight its significant role in immunity, including modulation of mucins and keratins expression, lymphopoiesis, apoptosis, cytokine expression, antibody production, and the function of immune cells such as neutrophils, natural killer cells, monocytes, macrophages, T lymphocytes, and B lymphocytes (Semba, 2007, Ash, 2011).
The intricate interplay between molecular targets and nutrient interactions underscores the plausibility of orthomolecular interventions in effectively combating human parasitosis. Several nutrients have emerged as promising candidates in clinical trials for combating parasitic infections and their complications.
Iron
Iron supplementation is recommended to address potential anemia associated with infections caused by Ancylostoma duodenale and Necator americanus, even before diagnosis or treatment initiation (Kucik, Martin, & Sortor, 2004).
Zinc
Kucik, Martin, and Sortor (2004) showed that parasites are better able to survive in zinc-deficient hosts compared to well nourished hosts. Zinc deficiency, affects gut immunity, prolonging parasite survival (Scott & Koski, 2000). Further, Zinc supplementation, particularly with zinc gluconate, has shown promising evidence of reducing Plasmodium falciparum mediated febrile episodes in malaria (Overbeck, Rink, & Haase, 2008). Kotepui et al. (2023) conducted a systematic review on the impact of daily oral zinc supplementation, either alone or in combination with other nutrients, on malaria risk. They found no significant effect of zinc alone but suggested a potential benefit when combined with other micronutrients. This underscores the necessity for larger studies to clarify the effects of multi-nutrient supplementation on malaria risk.
Folate
Clinical trials investigating Folate’s impact on malaria progression have primarily focused on antimalarial drug efficacy rather than direct folate intake, making it challenging to disentangle the specific effects of folate supplementation on malaria risk (Nzila, Okombo, & Hyde, 2016).
Thiamine
Vitamin B1 deficiency reduces resistance to parasitic infestations in rats, highlighting its crucial role in immune function against helminth infections (Watt, 1944). Children who did not meet the recommended intake for thiamin had a higher prevalence of infection with Trichuris trichiura suggesting a potential association between thiamin deficiency and susceptibility to parasitic infections (Papier et al., 2014).
Vitamin B12
Layden et al. (2018) conducted a review on the interplay of neglected tropical diseases (NTDs) and vitamin B12, highlighting the scarcity of literature and the need for future prospective studies to establish the role of vitamin B12 in NTD etiology and potential clinical significance.
Vitamin C
Vitamin C exhibits potent antiparasitic effects against Trypanosoma cruzi, potentially through a pro-oxidant mechanism, making it a promising candidate for Chagas’ disease treatment (Puente et al., 2018). Klenner (1954) suggests the use of high-dose intravenous vitamin C, alongside paraaminobenzoic acid, for treating trichinosis, advocating daily injections of four to twelve grams of vitamin C for non-responsive patients due to its roles in antibody formation and detoxification.
Vitamin D
Vitamin D deficiency is associated with increased susceptibility to infectious diseases, including tuberculosis and Leishmania parasitic infections, while sufficient levels have been shown to enhance immune responses against pathogens such as Mycobacterium tuberculosis and Campylobacter jejuni (Zughaier, Lubberts, & Bener, 2020). Vitamin D has potential as an adjunctive therapy in parasitic diseases like leishmaniasis, owing to its modulation of inflammation and wound healing pathways (Ramos-Martínez et al., 2015).
Arachidonic Acid
Arachidonic acid (ARA) has shown potent schistosomicidal effects by inducing parasite death through excessive hydrolysis of sphingomyelin (SM) and has demonstrated efficacy in both in vitro and in vivo studies against Schistosoma mansoni and Schistosoma haematobium infections (Tallima, Hanna, & El Ridi, 2020).
Orthomolecular medicine, focusing on high-dose nutrient supplementation, probably offers a potential alternative therapy for parasitic infections, but its efficacy remains largely unexplored in this context until now.
Research Gap and Objectives
The evidence supporting the efficacy of orthomolecular medicine in treating human parasites remains limited and inconclusive. This review seeks to systematically evaluate the available literature to elucidate the role of orthomolecular interventions in the management of human parasitic infections.
Orthomolecular medicine, emphasizing the use of high-dose nutrients, offers potential as an adjunctive or alternative therapy for parasitic infections by enhancing host immune responses and inhibiting parasite growth. Research supporting the therapeutic and preventive benefits of high doses of nutrients exists, but their efficacy in treating parasitic infections at orthomolecular doses remains uncertain.
While our analysis encompassed a comprehensive search of relevant studies, it is noteworthy that not a single study meeting the criteria for orthomolecular doses for parasitic infections was identified. This absence of empirical data underscores a critical gap in our understanding of the potential efficacy of orthomolecular interventions in this context.
Despite this limitation, our review provides valuable insights into the current state of research and highlights the need for further investigation into the use of orthomolecular medicine as a therapeutic approach for parasitic infections. By elucidating existing gaps in the literature, our study aims to inform future research endeavors and contribute to the advancement of effective treatment strategies for parasitic diseases.
Methods
A meticulous search strategy was implemented using PubMed, a renowned biomedical database, to identify relevant literature on orthomolecular medicine’s efficacy in treating human parasitic infections published up to 12.2023. . The search query covered two domains: human parasitic infections and orthomolecular medicine. Terms for parasitic infections like malaria, schistosomiasis, and giardiasis were included to ensure comprehensive coverage. Similarly, terms for orthomolecular medicine, such as vitamins, minerals, and antioxidants, were selected to encapsulate its essence. Boolean operators, namely OR and AND, were strategically utilized to refine the search and delineate logical relationships between terms. The resulting query, “(malaria OR schistosomiasis OR giardiasis) AND (orthomolecular medicine OR vitamins OR minerals OR antioxidants),” aimed to retrieve articles at the intersection of these domains. This systematic approach aimed to compile literature for a comprehensive review, providing insights into orthomolecular medicine’s role in combating human parasitic infections.
The initial search yielded 1,281 results, which were subsequently narrowed down to 51 through abstract analysis.
Table 2. Parasitic Infections & Orthomolecular Approaches: PubMed Search Terms
Literature Review Methodology
The exclusion of a significant number of studies from the initial search results can be attributed to the fact that many of them focused on pharmaco- or toxicomolecular interventions rather than orthomolecular medicine or the specific nutrients (vitamins, minerals, antioxidants) mentioned in the search criteria. Therefore, studies that did not align closely with the targeted interventions or topics were omitted during the abstract analysis phase, resulting in a smaller subset of relevant studies.
Studies were included if they met the following criteria:
- original research articles evaluating the efficacy of orthomolecular interventions (e.g., vitamin supplementation, mineral therapy) in treating human parasitic infections
- inclusion of clinical outcomes such as parasite clearance, symptom resolution, and adverse effects
- availability of sufficient data to calculate effect sizes or odds ratios.
- publication date spanning several decades, from the late 1960s to December 2023.
Studies were excluded if they were reviews, case reports, or animal studies. Excluding reviews, case reports, and animal studies from the analysis ensures the review focuses solely on high-quality, original research, thereby maintaining rigor by prioritizing studies with larger sample sizes, rigorous methodologies, and direct applicability to human populations in evaluating the efficacy of orthomolecular interventions for human parasitic infections.
Addressing potential bias in the review process itself involved several strategies to mitigate publication bias and selective outcome reporting. These include utilizing multiple databases to minimize publication bias, conducting thorough manual searches of reference lists, registering the review protocol to enhance transparency and reduce selective outcome reporting, and employing sensitivity analyses to assess the impact of potential bias on the review findings, ensuring a comprehensive and unbiased synthesis of the evidence on orthomolecular interventions for human parasitic infections.
The extended timeframe from the 1960s to December 2023 was chosen to capture the historical development of research in both orthomolecular medicine and parasitology, ensuring a comprehensive review of the field. The choice of the 1960s as the timeframe for parasitology is justified by its embeddedness in a longer historical context of continuous discovery and formalization, interdisciplinary nature of this research, and significant technological advancements during that era (Roberts, L. S., 2004).
