An Expert Report on Olive Oil (DB09567) as a Biopharmaceutical Agent and Therapeutic Modality

Executive Summary

Olive Oil (DB09567), a substance long recognized for its culinary and traditional medicinal value, has emerged as a significant agent within the modern pharmaceutical and biotechnology landscape. This report provides a comprehensive scientific and clinical analysis of olive oil, elucidating its multifaceted role that extends far beyond basic nutrition. Classified by DrugBank as a "Biotech" product, its identity in contemporary medicine is defined by two primary functions: first, as an Active Pharmaceutical Ingredient (API) in parenteral nutrition emulsions, providing essential calories and fatty acids to vulnerable patient populations; and second, as a critical, high-purity excipient and raw material that enables the formulation and manufacture of advanced therapeutics, including sensitive biologic drugs and sustainable vaccine adjuvants.

The pharmacological profile of olive oil is uniquely dualistic. Its major lipid components, predominantly glycerides of oleic acid, provide metabolic energy. However, its therapeutic potency is largely derived from a complex mixture of minor bioactive constituents, including the potent anti-inflammatory phenol oleocanthal, which exhibits a mechanism of action similar to ibuprofen, and a broad array of other polyphenols like hydroxytyrosol and oleuropein that confer significant antioxidant and immunomodulatory effects. This synergistic interplay of components underpins the extensive clinical evidence supporting its use.

Clinical investigations, most notably large-scale trials such as the PREDIMED study, have robustly established the role of extra virgin olive oil in reducing the risk of cardiovascular disease and managing systemic inflammation. Evidence for its application in metabolic disorders, such as type 2 diabetes, is also growing. While research in other areas like neurodegenerative disease and infectious disease is more nascent, it highlights the broad therapeutic potential of its bioactive compounds.

This report further details the critical applications of highly purified, "Super Refined" olive oil in biopharmaceutical manufacturing, where its inertness is essential for stabilizing fragile protein-based drugs like monoclonal antibodies. It also examines its pivotal role as a sustainable source of phytosqualene, a key component in modern vaccine adjuvants, thereby contributing to global public health security. A thorough review of its safety profile confirms its general safety for oral and topical use but underscores the specific clinical risk of Fat Overload Syndrome associated with its intravenous administration and highlights significant, albeit sometimes conflicting, data regarding its interactions with anticoagulant, antihypertensive, and antidiabetic medications. By synthesizing physicochemical data, pharmacological mechanisms, clinical evidence, and biomanufacturing applications, this report presents a holistic and nuanced understanding of olive oil as a complex, valuable, and evolving entity in pharmaceutical science.

Section 1: Identification and Physicochemical Properties

A precise and comprehensive understanding of the identity and physicochemical properties of olive oil is fundamental to its application in a pharmaceutical context. This section consolidates technical data to establish a definitive profile for Olive Oil (CAS 8001-25-0), distinguishing between various grades and highlighting the specifications relevant to formulation, manufacturing, and regulatory compliance.

1.1. Nomenclature and Regulatory Identifiers

The systematic identification of olive oil within scientific and regulatory databases is crucial for accurate literature retrieval, quality control, and global pharmaceutical commerce.

• Generic Name: Olive oil [1]
• DrugBank Accession Number: DB09567 [1]
• CAS (Chemical Abstracts Service) Number: 8001-25-0 [2]
• EC (European Community) Number: 232-277-0 [4]
• Synonyms: Common synonyms include "Olive oil (edible)" and the Latin pharmacopoeial name "Oleum Olivarum".[2]
• DrugBank Classification: Olive oil is categorized within DrugBank under the Type "Biotech" and Modality "Other Biologics," with its status listed as "Approved" and "Investigational".[1] This classification is not arbitrary but is rooted in its complex, multi-component nature derived from a biological source and its critical role in enabling the formulation of biologic drug products. As a substance derived from a living organism that cannot be fully characterized by simple chemical structure and whose quality is dependent on the manufacturing process, it aligns with the broader definitions of biological and biotech products.[5]

1.2. Commercial Formulations and Brand Names

Olive oil is a component in a diverse range of commercial pharmaceutical and cosmetic products, demonstrating its versatility as both an active ingredient and an excipient.

• Parenteral Nutrition Formulations: In its role as an API for clinical nutrition, olive oil is a key component of lipid emulsions. Commercially available brand names for these products include Clinoleic, Clinolipid, Olimel, and Periolimel.[1] These formulations are often complex mixtures, combining olive oil with other lipid sources like soybean oil to provide a balanced profile of fatty acids for patients unable to receive nutrition orally or enterally.[1] The approval of these products for use in all age groups, including neonates, underscores the stringent quality and safety standards required for pharmaceutical-grade olive oil.[1]
• Topical and Other Formulations: Olive oil is widely used as an excipient in a variety of dosage forms for topical, cutaneous, and even vaginal administration. Marketed products include oils, sprays, lipsticks, soaps, and mists, where it functions as an emollient, solvent, or vehicle.[1]

1.3. Chemical Composition and Principal Constituents

Olive oil is a complex natural mixture, whose properties are defined by both its major and minor components.

• Primary Composition: Approximately 98-99% of olive oil consists of triacylglycerols, which are esters of glycerol and fatty acids.[10] The fatty acid profile is dominated by the monounsaturated omega-9 fatty acid, oleic acid, which typically constitutes 55-83% of the total. Other significant fatty acids include the polyunsaturated omega-6 fatty acid, linoleic acid (7.5-20%), and the saturated fatty acid, palmitic acid.[1]
• Minor Components: The remaining 1-2% of olive oil is an intricate amalgam of over 200 other chemical compounds that significantly contribute to its stability, sensory characteristics, and pharmacological activity.[10] This fraction includes:
• Hydrocarbons: Notably squalene.
• Tocopherols: Including Vitamin E.
• Sterols: Such as beta-sitosterol.
• Pigments: Chlorophylls and carotenoids (e.g., beta-carotene).
• Bioactive Phenols (Polyphenols): This is a critically important class of compounds responsible for many of olive oil's therapeutic effects. Key examples include simple phenols (tyrosol, hydroxytyrosol), secoiridoids (oleuropein), and other unique molecules like oleocanthal.[10]

The concentration and profile of these minor components are highly dependent on the olive cultivar, ripeness at harvest, climate, and extraction method, which is why extra virgin olive oil (EVOO), obtained by cold pressing, is significantly richer in these bioactive compounds than refined olive oils.[10]

1.4. Physical and Chemical Characteristics

The physical and chemical properties of olive oil are essential for its handling, formulation, and storage. Data from various Safety Data Sheets (SDSs) reveal a general profile, though some variability exists, likely due to differences in the grade and purity of the tested material. This variability underscores the importance of sourcing well-characterized, pharmacopoeial-grade oil for pharmaceutical applications. For instance, reliance on a generic CAS number is insufficient for ensuring batch-to-batch consistency; formulators must specify materials compliant with relevant monographs (e.g., EP, USP) to guarantee predictable performance and safety.[3]

The table below consolidates these properties from multiple sources.

Property	Value/Range	Source(s)
Physical State	Liquid, clear, viscous	13
Appearance	Yellow, dark yellow, or green oil	4
Odor	Light oil odor, characteristic odor, or odorless	2
Solubility	Soluble in ether, chloroform, carbon disulfide; sparingly soluble in alcohol	16
Specific Gravity	0.910–0.918	2
Melting Point	Reported values range from -41 °C to 0 °C	2
Flash Point	Reported values range from 113 °C (closed cup) to 225 °C (437 °F)	2
Autoignition Temp.	343 °C	15
Stability	Stable under normal conditions. Light sensitive. Shelf life can be indefinite if stored in a tightly closed container.	14
Incompatible Materials	Strong oxidizing agents, acids	4
Hazardous Combustion	Carbon Monoxide (CO), Carbon Dioxide (CO2​)	2

Section 2: Pharmacology and Bioactive Constituents

The pharmacological profile of olive oil is complex, arising from the distinct and synergistic actions of its major lipid components and its diverse array of minor bioactive constituents. While the fatty acids provide essential nutrition and modulate cellular functions, the phenolic compounds exert potent, targeted effects on various physiological pathways. This dual activity explains olive oil's utility in both clinical nutrition and as a therapeutic agent for chronic diseases.

2.1. Pharmacodynamics in Clinical Nutrition

In the clinical setting, the primary approved use of olive oil is as a component of parenteral nutrition (PN) emulsions.[1]

• Energy and Essential Fatty Acid Source: The triacylglycerols in olive oil serve as a dense source of calories for patients who cannot absorb nutrients through the gastrointestinal tract. Upon administration, these fatty acids become a primary substrate for energy production in tissues throughout the body via the metabolic process of beta-oxidation.[1]
• Structural and Signaling Roles: Beyond providing energy, the fatty acids are incorporated into cell membranes, where they are crucial for maintaining structural integrity and fluidity. They also serve as precursors for the synthesis of eicosanoids, such as prostaglandins and leukotrienes, which are critical signaling molecules involved in inflammation, blood clotting, and immune responses.[1] Formulations like Clinolipid are specifically indicated for all age groups, including vulnerable preterm neonates, highlighting the essentiality of these fatty acids for growth and development.[1]

2.2. Pharmacokinetics and Metabolism

The metabolic fate of olive oil's components varies based on their chemical nature.

• Lipid Component: The triacylglycerols are hydrolyzed into fatty acids and glycerol. The fatty acids undergo beta-oxidation, ultimately being metabolized to carbon dioxide and water, with the release of energy.[1] Carbon dioxide is exhaled, while water is eliminated through various routes including respiration, perspiration, and urination. A portion of lipids may also be excreted in the bile.[1]
• Polyphenol Component: The pharmacokinetics of the phenolic compounds are more complex. Following ingestion, they are absorbed and undergo extensive metabolism in the intestine and liver. The resulting metabolites, which are typically methylated, sulfonated, or glucuronidated, are then excreted, primarily in the urine.[12] Crucially, in vitro studies have demonstrated that these metabolites often retain or even possess enhanced biological activity, suggesting that the systemic therapeutic effects of olive oil consumption are mediated by this suite of metabolic products, not just the parent compounds.[17]

2.3. The Therapeutic Role of Oleic Acid

Oleic acid, the most abundant fatty acid in olive oil, is not merely an inert calorie source but an active molecule with pleiotropic effects on health.

• Cardiovascular Effects: A large body of evidence links oleic acid consumption to improved cardiovascular health. Mechanistically, it has been shown to help lower levels of low-density lipoprotein (LDL) cholesterol ("bad" cholesterol) while maintaining or increasing high-density lipoprotein (HDL) cholesterol ("good" cholesterol).[18] Its hypotensive effect has been attributed to its ability to modulate the lipid composition of cell membranes, which in turn influences G protein-mediated signaling pathways that regulate vascular tone.[19]
• Anti-inflammatory and Immunomodulatory Effects: Oleic acid exhibits significant modulatory effects on the immune system. It can reduce inflammation and has been shown to enhance the immune response to pathogens by influencing the function of key immune cells like macrophages and lymphocytes.[20] It also plays a role in promoting wound healing and skin regeneration.[18]
• Metabolic and Anti-Cancer Properties: Research suggests that diets rich in oleic acid may contribute to a reduction in abdominal fat and improve insulin sensitivity, thereby helping to prevent type 2 diabetes.[18] Furthermore, some preclinical studies indicate that oleic acid may possess anti-cancer properties by inhibiting the proliferation and migration of cancer cells and inducing apoptosis (programmed cell death).[18]

2.4. Oleocanthal: A Potent Anti-Inflammatory and Neuroprotective Phenol

Oleocanthal is a unique phenolic compound found exclusively in virgin olive oils and is responsible for the peppery or stinging sensation in the back of the throat, a hallmark of high-quality EVOO.[22] Its pharmacological properties are particularly compelling.

• Anti-inflammatory Mechanism: The most remarkable property of oleocanthal is its action as a natural non-steroidal anti-inflammatory drug (NSAID). It is a non-selective inhibitor of both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes.[22] This mechanism is identical to that of ibuprofen and is responsible for its ability to reduce the production of pro-inflammatory prostaglandins. While the amount of oleocanthal in a typical daily serving of EVOO (e.g., 50 g) provides an anti-inflammatory effect equivalent to only about 10% of a standard adult ibuprofen dose, the long-term, daily consumption of this compound is hypothesized to contribute significantly to the low incidence of chronic inflammatory diseases in populations adhering to a Mediterranean diet.[22]
• Neuroprotective Effects: Oleocanthal has shown significant promise in preclinical models of neurodegenerative diseases, particularly Alzheimer's disease. It has been found to interfere with the pathological aggregation of both amyloid-beta (Aβ) and tau proteins, the two key hallmarks of Alzheimer's.[25] It appears to enhance the clearance of Aβ from the brain and prevent tau from forming neurofibrillary tangles, in addition to reducing associated neuroinflammation.[22]
• Anti-Cancer Activity: In vitro studies have revealed that oleocanthal possesses potent and selective anti-cancer properties. It can induce rapid apoptosis in a variety of human cancer cell lines (including breast, prostate, and colon) by causing lysosomal membrane permeabilization, which releases enzymes that kill the cell.[22] Remarkably, this effect appears to be selective for cancer cells, as healthy, non-cancerous cells are left unharmed.[22] This selective cytotoxicity makes oleocanthal a highly attractive candidate for further investigation as a potential chemotherapeutic agent.

2.5. The Antioxidant and Immunomodulatory Effects of Polyphenols

Beyond oleocanthal, EVOO contains a rich diversity of other polyphenols, such as hydroxytyrosol, tyrosol, and oleuropein, which act collectively to provide broad health benefits.[27]

• Antioxidant Mechanism: The primary mechanism of these compounds is their potent antioxidant activity. They can directly scavenge and neutralize harmful reactive oxygen species (ROS), thereby protecting cells, lipids, proteins, and DNA from oxidative damage.[27] This protective effect on blood lipids is well-established and forms the basis of an approved health claim by the European Food Safety Authority (EFSA), which states that "olive oil polyphenols contribute to the protection of blood lipids from oxidative stress".[30]
• Broad Therapeutic Effects: Through their antioxidant and anti-inflammatory actions, this class of polyphenols contributes to a wide spectrum of health-promoting effects, including anti-atherogenic, anti-thrombotic, and anti-mutagenic properties.[27] They have been linked in numerous studies to a reduced risk of cardiovascular disease and type 2 diabetes.[32]
• Immunomodulation: Olive oil polyphenols can also modulate the activity of the immune system, for example, by influencing the proliferation of white blood cells and the production of signaling molecules (cytokines) that orchestrate immune responses.[27]

The overall therapeutic efficacy of high-quality EVOO can be understood as a result of a synergistic "entourage effect." The major lipid components like oleic acid provide a foundational benefit by modulating cell membranes and metabolic pathways, while the minor but highly potent bioactive phenols like oleocanthal and hydroxytyrosol exert targeted effects on specific enzymes and signaling cascades. The combined action on multiple, overlapping pathways related to inflammation, oxidative stress, and cell signaling is likely greater than the sum of the individual parts, explaining the consistent and broad health benefits observed in clinical and epidemiological studies. This complex interplay solidifies the status of EVOO not just as a healthy fat, but as a functional food with drug-like properties.

Section 3: Clinical Evidence and Therapeutic Investigations

The therapeutic potential of olive oil, suggested by its rich pharmacological profile, has been the subject of extensive clinical investigation. The available evidence ranges from large-scale, long-term epidemiological studies and randomized controlled trials to smaller, early-phase exploratory studies across a variety of indications. A clear "evidence gradient" exists, with robust support for its role in cardiovascular and inflammatory diseases, and more preliminary but promising data in other areas. This section systematically reviews the clinical trial data for Olive Oil (DB09567) and related interventions.

3.1. Cardiovascular and Metabolic Diseases

The most compelling clinical evidence for olive oil's health benefits lies in the prevention and management of cardiovascular and metabolic disorders.

• Major Clinical Trials and Epidemiological Studies:
• PREDIMED Study: The landmark PREvención con DIeta MEDiterránea (PREDIMED) trial, a multicenter randomized trial in Spain, provided powerful evidence. It demonstrated that a Mediterranean diet supplemented with extra virgin olive oil (at least 4 tablespoons per day) was associated with a 30% reduction in the incidence of major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes) compared to a control diet recommending reduced fat intake.[30]
• U.S. Cohort Studies: Long-term observational studies in the United States, including the Nurses' Health Study and the Health Professionals Follow-up Study, have corroborated these findings. An analysis of these cohorts found that higher olive oil intake (more than 1/2 tablespoon or 7 g/day) was associated with a 19% lower risk of cardiovascular disease mortality and a 19% lower risk of all-cause mortality.[30] The study also showed that replacing animal fats like butter and margarine with olive oil was associated with significant health benefits.[35]
• Meta-Analyses: Numerous meta-analyses have synthesized the available data, consistently concluding that higher olive oil consumption is inversely associated with the risk of cardiovascular disease, stroke, and overall mortality.[30] One such analysis found that an increase of 25 g/day in olive oil consumption was linked to an 8% lower risk of cardiovascular disease.[30]
• Specific Indications:
• Hypertriglyceridemia: A completed Phase 3 clinical trial (NCT01408303) investigated olive oil as part of a combination therapy with a statin for patients with hypertriglyceridemia, aiming to reduce non-HDL cholesterol levels.[38]
• Type 2 Diabetes Mellitus: A completed Phase 1 trial (NCT03544411) evaluated the effects of olive oil on glycemic control, lipid profiles, and antioxidant levels in patients with type 2 diabetes.[39] Another trial (NCT03447301) was specifically designed as a randomized controlled trial to assess the impact of daily EVOO supplementation on glycated hemoglobin (HbA1c) levels in diabetic patients.[40]

3.2. Inflammatory and Immunological Conditions

Mechanistically linked to its cardiovascular benefits, the anti-inflammatory properties of olive oil are also supported by direct clinical evidence.

• Clinical Trials on Inflammation: A completed Phase 4 trial (NCT00600912) examined the influence of a complex lipid emulsion containing olive oil, fish oil, and medium-chain triglycerides on the inflammatory response and hepatic function in a clinical setting.[41] The inclusion of olive oil in such a formulation for post-market surveillance reflects its established role in clinical nutrition for modulating inflammation.
• Meta-Analyses on Biomarkers: Several systematic reviews and meta-analyses have focused on the effect of olive oil consumption on specific biomarkers of inflammation and oxidative stress. These studies consistently report that regular intake of EVOO, particularly those with high polyphenol content, leads to a statistically significant reduction in key inflammatory markers, including C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α).[43] Additionally, consumption is associated with a decrease in oxidized LDL (a key factor in atherosclerosis) and an improvement in endothelial function, as measured by flow-mediated dilatation.[43]

3.3. Neurological and Psychiatric Disorders

The application of olive oil in neurological conditions is an emerging area of research, primarily driven by the promising preclinical data on its neuroprotective components. The clinical evidence is currently in earlier stages.

• Agitation Related to Dementia: A completed Phase 2 trial (NCT03328676) investigated the use of medical cannabis for dementia-related agitation. In this study, olive oil was used as a component of the formulation, likely as a carrier oil for the active cannabinoids.[47]
• Mania: A completed Phase 2 trial (NCT00917501) explored the neurochemical effects of omega-3 fatty acids in adolescents at high risk for mania. Olive oil was used in conjunction with fish oil in the study design, potentially as a comparator or part of the active formulation.[48]

It is important to note that in these neurological trials, the role of olive oil was often secondary (e.g., as a vehicle or comparator) rather than as the primary investigational agent. This context-dependent role complicates the direct attribution of any observed effects solely to olive oil. Future research would benefit from trial designs that isolate olive oil as the sole variable against an appropriate control to better delineate its specific contributions.

3.4. Other Investigational Areas

The therapeutic hypotheses for olive oil extend to other fields, including oncology and infectious diseases, though the clinical evidence is mixed.

• Oncology: A Phase 2 trial investigating olive oil for the treatment of Head and Neck Cancer was terminated.[49] The reasons for termination are not specified in the available data but could range from lack of efficacy to safety concerns or logistical issues. This represents a significant, albeit negative, data point in translating preclinical anti-cancer promise to the clinic.
• Infectious Disease (HPV): A completed Phase 3 trial (NCT02346227) evaluated a formulation containing calcium oxide and olive oil for the treatment of Human Papillomavirus (HPV)-associated lesions of the uterine cervix.[50] The completion of a Phase 3 trial in this niche indication suggests a potentially promising application that warrants further analysis of the study's outcomes.

The following table provides a consolidated summary of the key clinical trials identified.

ClinicalTrials.gov ID	Indication(s)	Phase	Status	Purpose	Role of Olive Oil	Key Drugs in Trial	Source(s)
NCT00600912	Inflammatory Reaction, Liver Functions	4	Completed	Treatment	Component of lipid emulsion	Fish oil, MCTs, Omega-3s, Soybean oil	41
NCT01408303	Hypertriglyceridemias, Cardiovascular Diseases	3	Completed	Treatment	Component of intervention	Statin (unspecified)	38
NCT02346227	Papilloma Viral Infection, Cervical Dysplasia	3	Completed	Treatment	Component of formulation	Calcium oxide	50
NCT03328676	Agitation Related to Dementia	2	Completed	Treatment	Vehicle/Component	Medical Cannabis	47
NCT00917501	Mania	2	Completed	Treatment	Component/Comparator	Fish oil	48
Not Applicable	Head and Neck Cancer	2	Terminated	Treatment	Investigational Agent	Not Applicable	49
NCT03544411	Type 2 Diabetes Mellitus	1	Completed	Treatment	Investigational Agent	Not Applicable	39

Section 4: Applications in Biopharmaceutical Formulations and Manufacturing

The classification of olive oil as a "Biotech" product is most clearly justified by its critical and evolving role in the manufacturing of modern biopharmaceuticals. Beyond its direct therapeutic effects, highly purified grades of olive oil function as enabling technologies, solving key challenges in the formulation of sensitive drugs and the sustainable production of vaccine components. This section details these advanced applications.

4.1. Olive Oil as a Pharmaceutical Excipient

Olive oil has a long history of use as a versatile excipient in a wide array of pharmaceutical dosage forms. Its physicochemical properties allow it to serve multiple functions:

• Solvent and Vehicle: It is used as a solvent or vehicle in injectable, oral, and topical formulations for lipophilic (fat-soluble) drugs, enhancing their solubility and delivery.[3]
• Emollient and Lubricant: In dermatological and cosmetic products, it acts as an emollient, lubricant, and demulcent, providing moisturizing and soothing properties.[6]
• Penetration Enhancer: Oleic acid, its primary component, can act as a percutaneous absorption enhancer, facilitating the delivery of active drugs through the skin in topical formulations.[24]
• Nanoemulsion Formation: It serves as the lipid phase in the creation of nanoemulsions. These advanced drug delivery systems consist of nanoscale oil droplets dispersed in an aqueous phase, which can significantly improve the stability and bioavailability of poorly soluble APIs, such as the antifungal agent terbinafine hydrochloride.[51] Studies have also shown that excipient emulsions formulated with olive oil can enhance the bioaccessibility of lipophilic nutrients like carotenoids.[52]

4.2. "Super Refined" Olive Oil for Biologics and Injectables: Enhancing Stability and Safety

The advent of biologic drugs—large, complex molecules such as monoclonal antibodies and therapeutic proteins—has created new and demanding challenges for formulation science. These molecules are exquisitely sensitive to their chemical environment. This has led to the development of ultra-high-purity excipients, where olive oil has become a key example of a broader trend where excipients are no longer inert fillers but are active, performance-enhancing components.

• The Challenge of Impurities: Standard compendial-grade excipients, while meeting basic purity standards, can contain trace amounts of reactive impurities like peroxides, aldehydes, and residual metal catalysts. For sensitive biologics, these impurities can be catastrophic, initiating oxidative degradation pathways that lead to protein aggregation, loss of therapeutic potency, and the potential for increased immunogenicity in patients.[6]
• The "Super Refined" Solution: To address this, specialized manufacturers have developed proprietary, multi-step purification processes that remove these deleterious impurities to levels far below those specified in standard pharmacopoeias. The resulting "Super Refined™" olive oil is an essentially inert, high-purity lipid.[6]
• Critical Benefits for Biologics: Using this ultra-pure grade of olive oil in formulations provides several key advantages:

1. Enhanced API Stability: By eliminating the reactive species that trigger degradation, it protects the fragile biologic drug, enhancing its stability and extending the product's shelf life.[6]
2. Improved Safety: It minimizes the risk of cellular irritation and adverse patient reactions, which is particularly critical for injectable formulations that bypass the body's natural defense barriers.[6]
3. Endotoxin Control: These specialized grades are subject to LAL (Limulus Amebocyte Lysate) testing to ensure they meet the stringent bacterial endotoxin limits required for all parenteral products.[6]
4. Consistency: The purification process removes variability inherent in natural products, ensuring high batch-to-batch consistency, a cornerstone of pharmaceutical quality.[6]

4.3. A Sustainable Source for Vaccine Adjuvants

Olive oil plays a pivotal role at the intersection of sustainability, supply chain security, and public health through its connection to vaccine adjuvants.

• Squalene as a Potent Adjuvant: Squalene, a natural triterpene hydrocarbon, is the key component of several highly effective oil-in-water emulsion adjuvants, such as MF59 (used in influenza vaccines) and AS03. These adjuvants significantly boost the body's immune response to a vaccine's antigen, allowing for smaller doses of antigen per vaccine (dose-sparing) and inducing a stronger, broader, and more durable immune response. This is particularly critical during a pandemic, as it allows for the rapid production of more vaccine doses.[54]
• The Unsustainable Shark-Based Supply Chain: For decades, the primary commercial source of squalene was the liver oil of deep-sea sharks. This practice is ecologically devastating, contributing to the endangerment of several shark species, and raises ethical concerns.[55] Furthermore, shark-derived squalene carries the risk of contamination with persistent organic pollutants and potential pathogens that bioaccumulate in the shark's liver.[55]
• Olive Oil as a Sustainable Alternative: Olive oil is a major plant-based source of squalene, referred to as phytosqualene. While the concentration in crude olive oil is low (up to 0.5%), a byproduct of the refining process known as the deodorizer distillate is highly enriched in squalene (up to 80%), making industrial-scale extraction economically viable.[55] This provides a renewable, scalable, and ethically sourced alternative to shark squalene.
• Equivalence and Commercialization: Studies have confirmed that phytosqualene from sources like olive oil is functionally equivalent to shark-derived squalene in its adjuvating effect and offers benefits in terms of stability and purity.[55] This has led to the commercialization of plant-based squalene adjuvants, such as SqualVax Vegetal, which explicitly uses phytosqualene extracted from olive oil.[56] This transition directly strengthens the global vaccine supply chain by reducing reliance on a finite and problematic animal source.

4.4. Manufacturing under cGMP and Regulatory Compliance

For its use in pharmaceutical products, olive oil must be manufactured with the same rigor as any other API or critical excipient.

• cGMP Manufacturing: Leading suppliers produce pharmaceutical-grade olive oil (e.g., Refined Olive Oil IV) under current Good Manufacturing Practices (cGMP), in compliance with guidelines such as ICH-Q7 for Active Pharmaceutical Ingredients.[3] This involves validated processes, stringent quality control, and manufacturing in classified cleanroom environments to ensure purity and prevent contamination.[3]
• Regulatory Support: These high-quality grades are supported by comprehensive regulatory documentation to facilitate their inclusion in global drug product filings. This includes compliance with multiple major pharmacopoeias (USP/NF, Ph. Eur., JP, ChP), a Certificate of Suitability to the European Pharmacopoeia (CEP), and a Type IV Drug Master File (DMF) submitted to the U.S. Food and Drug Administration (FDA).[3] This robust regulatory framework provides formulators and manufacturers with the assurance of quality, safety, and global acceptability.

Section 5: Safety, Toxicology, and Contraindications

A comprehensive safety assessment of olive oil must differentiate between its various contexts of use, as the risk profile is highly dependent on the route of administration and the specific formulation. While generally regarded as safe for oral consumption and topical application, its use in intravenous formulations carries specific and significant risks that require careful clinical management.

5.1. Toxicological Profile and Handling Precautions

Data from multiple Safety Data Sheets (SDSs) for olive oil used in laboratory and industrial settings provide a baseline toxicological profile.

• Acute Toxicity and Irritation: Olive oil is generally considered to have low acute toxicity and is not classified as hazardous under OSHA standards.[2] Health injuries are not expected under normal conditions of use.[13] However, it may cause mild, transient skin and eye irritation upon direct contact, and inhalation of aerosolized mists may cause irritation to the respiratory tract.[13]
• Carcinogenicity and Genotoxicity: It is not listed as a carcinogen by major regulatory bodies such as IARC, NTP, or OSHA, and no information suggests mutagenic or reproductive toxicity.[2]
• Occupational Handling: Standard industrial hygiene and safety practices are recommended for handling bulk olive oil. This includes using personal protective equipment (PPE) such as goggles and gloves, ensuring adequate ventilation to avoid mist inhalation, and avoiding direct contact with skin and eyes.[13]
• Storage and Stability: It should be stored in tightly sealed containers in a cool, dry, well-ventilated area, away from direct light, heat, and incompatible materials like strong oxidizing agents and acids.[13]

5.2. Adverse Effects and Clinical Safety

The adverse effects observed in a clinical context differ significantly from the occupational hazards.

• Fat Overload Syndrome: This is the primary and most severe form of toxicity associated with the intravenous administration of olive oil as part of a lipid emulsion for parenteral nutrition.[1] It is a rare but potentially fatal complication characterized by a sudden deterioration in the patient's clinical condition. Symptoms include fever, anemia, leukopenia (low white blood cell count), thrombocytopenia (low platelet count), coagulation disorders, hyperlipidemia, fatty infiltration of the liver, deteriorating liver function, and central nervous system manifestations.[1] This syndrome underscores the critical need for careful dosing and monitoring of patients receiving total parenteral nutrition.
• Gastrointestinal Effects: When consumed orally in excessive amounts, olive oil can have a laxative effect, leading to mild and temporary digestive issues such as diarrhea, nausea, or stomach discomfort.[11]
• Allergenicity and Hypersensitivity: True IgE-mediated allergy to olive oil is exceedingly rare.[17] This is because the refining process removes most of the proteins that are typically responsible for allergic reactions.[58] Allergy to olive tree pollen, which causes seasonal respiratory symptoms, is far more common but is distinct from a food allergy.[58] There are isolated case reports of contact dermatitis or urticaria from topical application and, very rarely, anaphylaxis to olive fruit, which has been linked to sensitization to lipoproteins within the fruit rather than the oil itself.[60]

5.3. Contraindications and High-Risk Populations

While there are no absolute contraindications for the general dietary use of olive oil, caution is warranted in specific populations and clinical scenarios.

• Diabetes: Olive oil may lower blood glucose levels. Patients with diabetes, particularly those taking antidiabetic medications (e.g., insulin, glimepiride), should monitor their blood sugar closely when consuming medicinal quantities of olive oil to avoid hypoglycemia (abnormally low blood sugar).[18]
• Hypotension: Due to its potential to lower blood pressure, individuals taking antihypertensive medications should be cautious, as the additive effect could lead to hypotension (abnormally low blood pressure).[63]
• Surgery: It is often recommended that patients discontinue medicinal use of olive oil two weeks prior to scheduled surgery. This is due to its potential effects on blood glucose control and blood clotting, which could complicate the perioperative period.[64]
• Pregnancy and Lactation: While olive oil is generally recognized as safe (GRAS) when consumed as part of a normal diet, there is insufficient data on the safety of consuming large, medicinal amounts during pregnancy or breastfeeding. Therefore, such use should be avoided.[11]

5.4. Significant Drug-Drug Interactions

The potential for olive oil to interact with medications is a critical clinical consideration. A significant knowledge gap exists concerning its interaction with anticoagulants, as different authoritative sources present conflicting information. This discrepancy highlights an area requiring urgent further research to provide clear clinical guidance.

Interacting Drug/Class	Nature of Interaction	Potential Outcome	Source(s)	Clinical Recommendation
Anticoagulants / Antiplatelets (e.g., Warfarin, Apixaban, Clopidogrel, Heparin)	Pharmacodynamic	Conflicting Evidence: 1. Decreased Efficacy: DrugBank states that the therapeutic efficacy of these drugs can be decreased, implying an antagonistic or pro-thrombotic effect. 2. Increased Bleeding Risk: Other sources suggest olive oil may have its own antiplatelet/anticoagulant effects, potentially increasing the risk of bleeding and bruising when combined with these drugs.	1	Extreme caution is advised. Clinicians should be aware of the conflicting data. Close monitoring of coagulation parameters (e.g., INR for warfarin) and for signs of either thrombosis or bleeding is essential. Patients should not initiate or alter high-dose olive oil intake without consulting their healthcare provider.
Antihypertensive Drugs (e.g., Captopril, Amlodipine, Furosemide)	Pharmacodynamic	Additive hypotensive effect, potentially leading to an excessive drop in blood pressure (hypotension).	64	Monitor blood pressure closely, especially when initiating or increasing olive oil intake. Dose adjustment of the antihypertensive medication may be necessary.
Antidiabetic Drugs (e.g., Insulin, Metformin, Glyburide)	Pharmacodynamic	Additive hypoglycemic effect, potentially leading to an excessive drop in blood sugar (hypoglycemia).	18	Monitor blood glucose levels closely. Patients should be educated on the signs of hypoglycemia. Dose adjustment of the antidiabetic medication may be necessary.

Section 6: Historical Context and Traditional Medicinal Use

The contemporary scientific investigation into olive oil's therapeutic properties is not a new endeavor but rather the modern validation of millennia of empirical observation and traditional use. Its role as a medicinal agent is deeply embedded in the history of civilizations around the Mediterranean basin. This historical context provides a rich backdrop for understanding its enduring importance in human health.

6.1. Applications in Ancient Egyptian, Greek, and Roman Medicine

The use of olive oil as a therapeutic substance is documented in some of the earliest medical texts.

• Ancient Egypt: As early as 1550 BCE, the Ebers Papyrus, one of the oldest preserved medical documents, contains recipes for ointments and remedies using olive oil.[66] It was prescribed for a variety of ailments, including skin conditions like eczema and psoriasis, to soothe insect bites and stings, and to treat joint pain and eye infections.[66] Beyond medicine, it was a key ingredient in cosmetics and played a role in the sacred ritual of embalming.[66]
• Ancient Greece: The olive tree was held in sacred regard, and its oil was central to Greek culture and medicine. Hippocrates (c. 460–370 BCE), widely considered the "Father of Medicine," is reported to have documented over 60 medicinal uses for olive oil, including the treatment of skin diseases, wounds, and burns.[66] Greek athletes famously anointed their bodies with olive oil before competition, believing it conferred strength and protection, and it was also used as a base for perfumes.[69] Aristotle even described a contraceptive mixture containing olive oil.[67]
• Ancient Rome: The Romans inherited and expanded upon Greek medical knowledge. Roman physician Galen (c. 129–216 CE) is credited with inventing an early form of cold cream using olive oil as a primary ingredient to soothe the skin.[69] In a society without soap, Romans used olive oil for hygiene, rubbing it on their skin and then scraping it off with a tool called a strigil to remove dirt and grime, a practice that both cleansed and moisturized.[69]

6.2. Role in Traditional Mediterranean and Middle Eastern Folk Remedies

The legacy of these ancient practices continued through the centuries, becoming deeply ingrained in the folk medicine traditions of the Mediterranean and Middle East.

• Digestive Health: A common and enduring remedy across the Mediterranean is the consumption of a tablespoon of olive oil on an empty stomach to relieve constipation and promote digestive regularity. The fats are believed to lubricate the intestinal tract, easing the passage of stool.[66]
• Pain and Inflammation: The practice of massaging warm olive oil into sore joints and muscles to alleviate pain and inflammation is a traditional remedy that persists to this day.[66] This empirical use directly foreshadows the modern discovery of oleocanthal, the NSAID-like compound in EVOO.
• Regional and Cultural Practices: The specific applications varied by region. In Iraqi Jewish tradition, it was used for headaches and to improve appetite.[66] In Syria, it was recommended for women facing fertility challenges.[66] Healers in Tunisia and Algeria developed specialized massage techniques with olive oil for treating bone fractures and back pain.[66] The influential 11th-century Persian physician Avicenna, in his The Canon of Medicine, recommended olive oil for respiratory problems, fevers, and even for its calming effect on the nervous system to treat anxiety.[67]
• Antimicrobial Uses: Traditional medicine has long utilized olive oil for infections. This is now supported by modern research showing that its components, such as oleuropein, have antibacterial, antifungal, and antiviral properties and can be effective against pathogens like Helicobacter pylori, a bacterium that can cause stomach ulcers.[71]

This remarkable "ethno-pharmacological continuity"—the direct line from ancient empirical use to modern molecular validation—is a powerful theme in the story of olive oil. The conditions for which it was traditionally used (inflammation, skin ailments, infections, digestive issues) are precisely the areas where contemporary science has identified active compounds and confirmed mechanisms of action. This historical perspective validates its long-held status as a healing agent and provides a compelling rationale for its continued scientific exploration.

Section 7: Concluding Remarks and Future Perspectives

This comprehensive analysis reveals olive oil as a substance of remarkable complexity and utility, bridging the gap between ancient traditional medicine, modern clinical nutrition, and cutting-edge biopharmaceutical science. Its identity has evolved from a simple nutritional staple to a cGMP-manufactured Active Pharmaceutical Ingredient and a critical, high-performance component in the formulation of advanced biologic therapies.

7.1. Synthesis of Findings: From Nutritional Staple to Advanced Biopharmaceutical Component

The therapeutic value of olive oil is derived from a synergistic interplay between its major and minor constituents. The high concentration of oleic acid provides not only caloric energy but also confers direct benefits on cardiovascular and immune health. Simultaneously, the rich profile of minor phenolic components, particularly in extra virgin olive oil, exerts potent antioxidant, anti-inflammatory, neuroprotective, and anti-cancer effects. Oleocanthal, with its ibuprofen-like mechanism, stands out as a prime example of a natural compound with a well-defined, drug-like action.

The clinical evidence supporting olive oil's role in health is strongest and most mature in the realm of cardiovascular disease prevention and the modulation of systemic inflammation, backed by large-scale, long-term clinical trials and numerous meta-analyses. This establishes its role as a cornerstone of a therapeutic dietary pattern. The quality and grade of the oil are paramount; the superior therapeutic and functional benefits are consistently associated with high-polyphenol extra virgin olive oil over refined grades.

Furthermore, the emergence of "Super Refined" olive oil as an ultra-pure excipient marks a significant advancement in formulation science. By protecting sensitive biologic APIs from degradation, it functions as an enabling technology, underscoring its "Biotech" classification. Similarly, its role as a sustainable source for the vaccine adjuvant squalene places it at a critical nexus of environmental sustainability and global public health.

7.2. Gaps in Current Research and Directions for Future Investigation

Despite the wealth of knowledge, significant gaps and opportunities for future research remain. Addressing these will be crucial for fully realizing the therapeutic potential of olive oil and its derivatives.

1. Clarification of Drug Interactions: The diametrically opposed reports regarding the interaction between olive oil and anticoagulant/antiplatelet medications represent a critical area of uncertainty and a potential patient safety issue. Mechanistic studies are urgently needed to determine whether its net effect is pro- or anti-thrombotic when combined with these drugs and to elucidate the dose- and component-dependent factors that may be at play.
2. Clinical Validation of Minor Components: The preclinical evidence for compounds like oleocanthal in neurodegenerative diseases and cancer is exceptionally promising. The next critical step is to translate these in vitro and animal model findings into well-designed human clinical trials to establish efficacy and safety. This may require the development of high-purity, standardized extracts to deliver a consistent and therapeutic dose.
3. Standardization and Dosing for Therapeutic Use: To move beyond dietary recommendations and toward true pharmaceutical application, further research is needed to define optimal therapeutic doses of high-polyphenol EVOO or its extracts for specific conditions. The development of standardized formulations with guaranteed concentrations of key bioactive compounds (e.g., oleocanthal, hydroxytyrosol) is essential for ensuring reliable and reproducible clinical outcomes.
4. Head-to-Head Excipient Performance Studies: While the theoretical benefits of "Super Refined" olive oil are clear, rigorous formulation studies directly comparing its performance in stabilizing specific, commercially relevant biologic APIs against other high-purity excipients would provide invaluable data for formulators and further solidify its position as a premium component in high-value drug products.
5. Investigation of Terminated Trials: A deeper investigation into the reasons for the termination of the Phase 2 trial in head and neck cancer could yield important insights. Understanding whether the failure was due to a lack of efficacy, an unfavorable safety signal, or other logistical factors would provide valuable lessons for the design of future oncological studies involving olive oil-derived compounds.

In conclusion, olive oil (DB09567) is a multifaceted agent whose full potential is still being uncovered. Future research focused on these key areas will be instrumental in transitioning its potent bioactive components from a cornerstone of a healthy diet into targeted, evidence-based therapeutic interventions.

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