Given the not insignificant increase in global interest for metabolic therapies in general, and specifically, for Dr. Thomas Seyfried’s Press/Pulse protocol over the last 10 years, there is occasion to review where the state of the art stands now, in 2025, and perhaps gain some insight as to what we can anticipate evolving over the forthcoming 10 years with regard to disease management in Oncology.
Notably, understanding cancer as a disease of insufficient mitochondrial respiration correspondent to cells losing their energy production capacity via a downregulation or inhibition of Oxidative Phosphorylation, concurrent to an upregulation of compensatory mitochondrial Substrate Level Phosphorylation (fermentation) of glucose and glutamine, is not particularly new.
Learn more, here: Cancers_craving_for_sugar_an_opportunity_for_clinical_exploitation
and here: Exploiting_the_Achilles_heel_of_cancer
As such, Dr. Seyfried’s Press/Pulse protocol offers an opportunity, currently reserved primarily for those who elect to independently administrate it given that it is not yet part of establishment Oncology, to manage disease in a sustainable and non-toxic manner, both with, and in some instances, without, the Standard of Care.
Compellingly, since 1996, the case record has grown richly with demonstrations of the effectiveness of metabolic therapies, and now, in the epoch of social media, self-reporting of people’s experience with the Press/Pulse protocol is happening in real time.
Learn more, here: Ketogenic_diet_case_study_two_pediatric_patients
and here: Survival Outcomes of Metabolically Supported Chemotherapy
Worth considering in detail however, is that while there are any number of cases in the published scientific record whereby the control of glucose and ketones, such that glucose is consistently within or near the range of 3.0-3.5mMol/L (55-65mg/dL) and ketones are within or near the range of 4-7mMol/L, month after month (refer to Chapter 18 of Dr. Thomas Seyfried’s 2012 book, 'Cancer As A Metabolic Disease' for greater detail), is combined with some form of Standard of Care surgery, radiation, chemotherapy, immunotherapy and hormone ablatement therapy, there are very few cases wherein the entirety of the Press/Pulse protocol has been implemented, with or without the Standard of Care.
Included within the parameters of Dr. Seyfried’s Press/Pulse protocol, are the following interventions, implemented in concurrent and overlapping fashion.
Glucose and ketone control, such that glucose is consistently within or near the range of 3.0-3.5mMol/L (55-65mg/dL) and ketones are consistently within or near the range of 4-7mMol/L.
Hyperbaric Oxygen Therapy at 2.5AT, 3 times per week for 90 minutes, for 40 sessions, followed by a two-week break, prior to continuing, based on PET/CT scan or MRI results.
Mebendazole, 50mg/Kg, daily, or, on an interval of 4 days on, 3 days off, based on tolerance assessed by renal and hepatic blood markers, in context to effects normally correlated to Standard of Care chemotherapeutics and immunotherapies.
6-Diazo-5-Oxo-L-Norleucine, 0.2-0.4mg/Kg on Day 0, Day 4, Day 8, Day 12 (ergo, every 4th day, three days between each dose), followed by a two-week break, prior to repeating. One can also elect to intensify this regimen by increasing dosing (0.5mg/Kg to 0.9mg/Kg correspondent to 400mg Adenine (VitB4) daily and 30 grams of fiber daily (psyllium husk fiber, acacia root fiber, glucomannan fiber, soluble corn fiber, etc., pursuant to downregulating known side effects such as nausea and intestinal distress)), and the number of doses per cycle (six, rather than four, extending the cycle to Day 16 and Day 20), pursuant to overcoming payload to tissue loss due to oral administration.
Stress (cortisol) management, via a daily practice such as meditation, yoga, sauna, resistance training, PEMF, massage, such that one ensures control of cortisol by remaining consistently placid and serene, thereby inhibiting a corresponding rise in glucose.
Learn more, here: Ketogenic_diet_as_a_metabolic_vehicle_for_enhancing_the_therapeutic_efficacy_of_mebendazole
and here: Repurposing_Drugs_in_Oncology_mebendazole_as_an_anti_cancer_agent
and here: The_Ketogenic_Diet_and_Hyperbaric_Oxygen_Therapy_Prolong_Survival
For clarity, Press simply refers to those interventions which are performed chronically (i.e., every day), and Pulse simply refers to those interventions performed intermittently (i.e., not every day). Hence, Press components would be glucose and ketone control, as well as stress (cortisol) management. The utilization of Mebendazole could be either a Press or a Pulse component, based on tolerability. Hyperbaric Oxygen Therapy and the use of 6-Diazo-5-Oxo-L-Norleucine would constitute Pulse elements of the Press/Pulse protocol.
Learn more, here: Clinical_Research_Framework_for_Ketogenic_Metabolic_Therapy
and here: Press_Pulse_a_Novel_Therapeutic_Strategy_for_Disease_Management
Therefore, a limited, though growing number of individuals worldwide are now engaged, at varying levels of competency and success, in the coherent and effective implementation of the entire balance of Dr. Seyfried’s Press/Pulse protocol. Of particular salience to these efforts, are the challenges surrounding the control of glucose and ketones, such that they remain consistently within or near the zone of metabolic management.
Helpful to this consideration, is having a clear understanding of the following:
1 gram of Fat = 9 calories
1 gram of Protein = 4 calories
1 gram of Carbohydrate = 4 calories
Additionally, the understanding that ketogenic ratios (such as 1:1, 2:1, 3:1, 4:1) describe the relationship between grams of Fat (the number on the left hand side) and grams of Protein + Carbohydrate (the numbers on the right hand side, given that the caloric density of 1 gram of Protein is identical to that of 1 gram of Carbohydrate), and that ketogenic ratios are calculated by dividing the number of Fat grams by the number of Protein + Carbohydrate grams, will assist in a more precise organization for controlling metabolic response.
Furthermore, being in consistent possession of a forensic accounting of the exact number of Fat grams, Protein grams and Carbohydrate grams consumed on a per meal basis, will allow one to have clear insight into the relationship between these metabolic inputs (ergo, grams of macronutrients), and the corresponding outputs, namely, the resulting glucose and ketones numbers, as measured twice daily, once prior to the first meal of the day, and again just prior to the final meal of the day, though one can electively measure more frequently.
It is in this fashion that one can begin to accurately assess and analyze if in fact a disease management effect is being imposed via the therapeutic control of glucose and ketones along with the other elements of Press/Pulse, in context to follow up PET/CT scans or MRIs, at regular intervals.
As well, measuring out and preparing meals in advance, as well as eating at the same times and intervals each day, constitutes a crucial habituation for ensuring that metabolic response is predictable and consistent.
Learn more here: The_Effects_of_Diet_on_Prostate_Cancer
and here: Exploring_the_Feasibility_and_Effects_of_a_Ketogenic_Diet_in_Patients_with_CNS_Malignancies
Naturally, all of these considerations are open to scrutiny, not the least which is the burden of implementation required of the patient, as they must, in most instances, solely account for the organization and execution of the Press/Pulse protocol, in the absence of any partnership with their Oncologist.
Of even greater consequence, is the notable requirement to dramatically increase one’s scientific literacy, pursuant to being in a position to competently ingest, and coherently apply, the key information contained within the scientific literature.
One can begin this process, here: Studying_Studies_Dr._Peter_Attia_Master_Class
For example, this will allow one to carefully adjudicate key elements of crucial understanding relating to Press/Pulse protocol, such as the consideration as to whether or not tumor cells can ferment substrates other than glucose or glutamine for cellular energy production?
Keep in mind, that in order to proliferate and survive, cancer cells require the primary fuels glucose and glutamine to compensate for inhibition of, or insufficiency in, Oxidative Phosphorylation.
This respiratory impairment results in an overexpression of oncogenes (via an upregulation of Hexokinase II, concurrent to an inhibition of Cytochrome C, alongside a downregulation of mitochondrial diphosphatidylglycerol, otherwise known as Cardiolipin, among other mechanisms) and a correspondent inactivation of tumor-suppressor genes, all of which contribute to abnormal energy metabolism in tumor cells.
Notably, no substantive scientific evidence has directly demonstrated that the growth of any tumor cells, including but not limited to Circulating Tumor Cells, can occur in context to the deprivation of fermentable fuels, namely, glucose and glutamine.
As well, it is crucial to recognize that there are a number of metabolites that catabolize toward the citric acid cycle via succinyl-CoA, thus resulting in a form of energy production, mediated by a key caveat. Carefully considering the relevant biochemistry clearly demonstrates that only glutamine catabolism can yield a net ATP production through mitochondrial Substrate Level Phosphorylation, otherwise referred to as fermentation.
Of special importance, several metabolites other than glutamine do eventually converge toward succinyl-CoA. These are the amino acids:
-valine
-isoleucine
-methionine
-histidine
-threonine
-glutamine
-glutamate
-propionate
-thymine
-and odd-chain fatty acids
Crucially however, except for glutamate and glutamine, the catabolism of all other metabolites expends one or more high-energy phosphates during metabolic interconversions prior to becoming succinyl-CoA, thereby not contributing towards a net positive energy balance for the tumor cell.
Additional means of fermentation can also come from a conversion into glutamate (for example, from arginine and proline), or from other metabolites that catabolize toward alpha-ketoglutarate (such as glycine, serine, sarcosine, dimethylglycine through pyruvate, and fatty acids or leucine through acetyl-CoA). However, meaningful concentrations of these metabolites in the plasma or in the tumor microenvironment are substantially less than that of glutamine and are therefore unlikely to contribute to energy production in any consequential fashion.
Furthermore, confusion over the linking of Oxidative Phosphorylation to overall tumor cell oxygen consumption and an acute failure in both clinical Oncology and laboratory sciences to recognize the role of fermentation as a compensatory energy mechanism, have led many Oncologists and laboratory investigators to erroneously conclude that the Electron Transport Chain is in fact functioning normally in tumor cells.
Yet additional confusion emerges in part as a result of a misapprehension from observations that tumor cells might also ferment fatty acids or ketone bodies for energy production. Fats and ketone bodies however, are nonfermentable fuel sources that would require Oxidative Phosphorylation in order to produce net ATPs for a tumor cell.
Nevertheless there is nuance to consider here, insofar that unregulated inputs of fats and ketone bodies can in fact increase tumor cell glycolysis and glutaminolysis via uncoupling mechanisms. As such, one can plainly recognize that enhanced glucose and glutamine metabolism could account for an indirect effect from high-fat diets that are consumed in uncontrolled or unrestricted caloric amounts, and absent any consideration of the distribution of macronutrients on a per meal basis.
All this of course to emphasize the essential importance of being in possession of a thorough understanding of the underlying biological mechanisms of action with regard to tumor metabolism, such that one is in an optimal position to coherently and effectively implement Dr. Seyfried's Press/Pulse protocol.
Learn more here: Amino_Acid_and_Glucose_Fermentation_Maintain_ATP_Content_in_Mouse_and_Human_Malignant_Glioma_Cells
And here: Cancer_stem_cells_resist_glucose_deprivation
And here: Regulation_of_stem_like_cancer_cells_by_glutamine
And here: Substrate_balances_across_colonic_carcinomas
And here: Tumor_cell_culture_survival_following_glucose_and_glutamine_deprivation
This same method of thinking can be applied to evaluating Standard of Care options.
Just to put a fine point on the essential function of scientific literacy in order to shrewdly and effectively evaluate what the scientific literature, or for that matter, an Oncologist is communicating, one would benefit immensely by being in possession of a working understanding of what a Confidence Interval is, what a Hazard Ratio is, what a p value is, along with the crucial differences between relative risk reduction and absolute risk reduction, as well as a solid grasp of how to distinguish between the metrics of Disease Free Survivorship, Progression Free Survivorship, Overall Response Rate, and critically, Overall Survivorship, and finally, understand how to interpret a Kaplan-Meier survivorship curve.
For example, a limited review of some of the key longitudinal trials regarding Standard of Care patient outcomes as pertains to breast cancer, can be instructive.
Firstly, the highly relevant B04 trial (see below), describes key take-aways from the combinatorial effects of lumpectomy/mastectomy and radiation therapy. These are:
"Analysis of data demonstrated that there was a remarkable similarity in the incidence and rate of treatment failure (TF) or mortality between patients having some radiation variation, regardless of its degree or extent and those who were treated with no protocol variation."
"Almost all recurrences in clinically node-negative patients were at sites treated per protocol. In positive-node patients, supraclavicular and chest wall recurrences occurred in patients having acceptable radiation to those sites and axillary recurrences were equivalent in patients treated with or without deviations at that site."
"The findings from these investigations are not presented in order to indicate that the quality and quantity of radiation may be unimportant. They have been obtained under careful monitoring and the variations are within a relatively narrow range. Consequently, more general extrapolations from these must be made with circumspection. The observations do suggest, however, that there is some acceptable leeway in the use of radiation, at least for treatment of the extent of disease present in patients in this study. Moreover, they refute any consideration that the failure to demonstrate a significant advantage following the use of postoperative radiation in Protocol No. B-04 could be related to the variation and inadequacy of radiation employed in a proportion of the patients. They tend to substantiate the contention that factors [ergo, the cancer itself] other than the type of operative procedure employed or the precision of administration of radiation are important in determining the survival of women with breast cancer."
Now, let's take a look at the essential commentary from the B06 trial (see below):
"Regardless of the cohort, no significant differences were found in overall survival, disease-free survival, or survival free of disease at distant sites between the patients who underwent total mastectomy and those treated by lumpectomy alone or by lumpectomy plus breast irradiation. After 12 years of follow-up, the cumulative incidence of a recurrence of tumor in the ipsilateral breast was 35 percent in the group treated with lumpectomy alone and 10 percent in the group treated with lumpectomy and breast irradiation (P<0.001)."
Moving on to the B21 trial (see below), here's the punchline:
"With long-term follow-up, the previously observed small improvement in locoregional recurrence with the addition of radiation therapy remains. However, this does not translate into an advantage in Overall Survival, distant disease-free survival, or breast preservation. Depending on the value placed on local recurrence, Tamoxifen remains a reasonable option for women age ≥ 70 years with ER-positive early-stage breast cancer."
Finally, let's dial in the most substantive commentary from the EORTC boost trial (see below):
"After a median follow-up period of 10.8 years, a boost dose of 16 Gy led to improved local control in all age groups, but no difference in survival."
Hence, with these facts in hand, one is in a position to not only have a richer conversation with any Oncologist/Radiologist, but also make treatment decisions in full possession of what the anticipated consequences of any given choice are, when evaluating the Standard Of Care.
b04_breast_cancer_surgery_and_radiation_survivorship
So, where does all this leave someone who is currently facing a new diagnosis of cancer, or has been working to survive an existing cancer? Admittedly and soberingly, with a very steep hill to climb.
The coherent and effective implementation of Dr. Seyfried’s Press/Pulse protocol is simply not convenient or easy, particularly under conditions whereby a patient may have had to endure the spectacularly deleterious side effects of the Standard of Care for several months or years, notable exceptions to this being lower dose/toxicity potentiated or metronomic chemotherapy. Additionally, Press/Pulse is not covered by most insurance policies, and hence access to therapies will constitute a retail exercise.
That said, the growing global community of people who are independently pursuing Press/Pulse protocol do demonstrate, albeit anecdotally, that perhaps even imperfect implementation of adjuvant metabolic therapies can produce measurable and meaningful clinical results, in the form of statistically significant increases in Overall Survivorship as evidenced by PET/CT scans and MRIs, in contrast to only Standard of Care therapies, via comparison to known Kaplan-Meier survivorship curves for any given Standard of Care protocol.
Hence, this understanding offers us an opportunity to take action on one of Dr. Seyfried’s perennially and publicly solicited queries- namely, what would have to be true in order to cut the cancer death rate in half, over the next 10 years?
Given that the Oncology market (cancer diagnostics and treatments) in the United States is projected to increase from $81B in 2024 to $180B in 2033, this begs the question: what is the scale of underwriting and funding, along with private and philanthropic investment, that would have to occur for the clinically managed application of Dr. Seyfried’s Press/Pulse protocol, to sufficiently scale to begin to preempt the deaths from cancer of 700,000 people annually?
Relatedly, what is the most expeditious means of training Oncologists, and more broadly, Functional or Complementary Medicine physicians, D.O.s and Naturopaths, to effectively apply Press/Pulse protocol in their clinics, as an adjuvant therapy in context to the Standard of Care?
And lastly, who will be the first entrepreneur to create a successful global franchise of Press/Pulse clinics which offer the entire balance of metabolic therapies alongside the Standard of Care, all under one roof?
As with all revolutions, be they medical or social, they are typically initiated in modest fashion, by a relatively small group of people, in solidarity, coalescing and collaborating around a single, inescapable idea.
Survive.
