The Hybrid Orthomolecular Protocol is a structured therapeutic concept developed by researchers affiliated with the International Society for Orthomolecular Medicine (ISOM). The protocol focuses on cancer metabolism by targeting the mitochondrial–stem cell connection (MSCC) and cancer stem cells (CSCs), two factors closely associated with tumor persistence, resistance, and metastasis.
Rather than relying on a single intervention, this approach combines targeted nutrients, dietary strategies, and selected repurposed compounds. Together, these elements aim to support mitochondrial function while disrupting key energy pathways used by cancer cells, including glycolysis and glutaminolysis. By influencing inflammation, immune signaling, and cellular metabolism, the protocol seeks to weaken cancer cell survival mechanisms at multiple levels.
A central principle of the protocol involves reducing cancer cells’ dependence on glucose and glutamine. High-dose vitamin C, for example, increases oxidative stress selectively within malignant cells, impairing their energy production. At the same time, zinc and vitamin D support mitochondrial respiration, which may limit cancer stem cell activity and reduce cellular adaptability.
In addition, repurposed agents such as ivermectin and compounds from the benzimidazole class interfere with structural and metabolic pathways essential for cancer cell division and nutrient uptake. These effects may restrict access to critical energy sources, placing additional metabolic pressure on tumor cells.
It is important to note that therapeutic concentrations of vitamin C require intravenous administration. Mebendazole is included in this protocol due to its regulatory status, although it represents a broader class of benzimidazoles that also includes fenbendazole, which has been widely discussed in metabolic oncology research.
Key Components and General Directions
1. Vitamin C
Intravenous administration at approximately 1.5 g/kg per day, two to three times per week. Dosage may vary depending on cancer grade and patient tolerance.
2. Vitamin D
Dosing is adjusted based on serum levels:
- ≤ 30 ng/mL: 50,000 IU/day
- 30–60 ng/mL: 25,000 IU/day
- 60–80 ng/mL: 5,000 IU/day
The target level is approximately 80 ng/mL. Once reached, maintenance dosing of around 2,000 IU/day is typically used. Serum levels should be monitored every two weeks during high-dose phases and monthly thereafter.
3. Zinc
Approximately 1 mg/kg daily until serum levels reach the reference range of 80–120 μg/dL. Maintenance dosing is typically reduced to around 5 mg/day once adequate levels are achieved.
4. Ivermectin
- Low-grade cancers: 0.5 mg/kg, three times per week
- Intermediate-grade cancers: 1 mg/kg, three times per week
- High-grade cancers: 1–2 mg/kg daily
5. Mebendazole
- Low-grade cancers: 200 mg/day
- Intermediate-grade cancers: 400 mg/day
- High-grade cancers: 1,500 mg/day, or fenbendazole 1,000 mg three times per week
6. 6-Diazo-5-oxo-L-norleucine (DON)
- Intravenous or intramuscular: 0.2–0.6 mg/kg once daily
- Oral administration: 0.2–1.1 mg/kg once daily
DON may be used as an alternative to mebendazole or combined with it, depending on clinical considerations.
7. Ketogenic Diet
A low-carbohydrate, high-fat dietary pattern providing approximately 900–1,500 kcal per day, designed to reduce glucose availability.
8. Moderate Physical Activity
Engagement in aerobic exercise three times per week for 45–75 minutes. Activities may include cycling, swimming, running, or similar forms of sustained movement.
Dr. William Makis has commented on this protocol, highlighting its peer-reviewed focus on metabolic targeting using ivermectin and benzimidazoles. Additional technical details are available in the original ISOM publication .
