EP234: Born Free: Rethinking Chronic Illness Through Systems Biology - Part 2 - Joshua Leisk
In a Nutshell
The core message is that chronic illness (ME/CFS, long COVID, POTS) stems from a self-reinforcing spiral of mitochondrial dysfunction, sympathetic dominance, heavy metal buildup, biofilm expansion, and lymphatic blockage, which must be reversed through staged metabolic restoration rather than symptom management. The protocol prioritizes Stage 1 remineralization and glutathione/methylation support to rebuild glycogen, reduce oxidative stress, and calm the cell danger response before any antimicrobial or immune-stimulation work. Key practical takeaways include using active B-vitamin forms and non-oral delivery routes early, avoiding graded exercise until glycogen metabolism recovers, titrating citric acid and ionic minerals slowly to manage die-off, and only advancing to Stage 3 immune activation once PEM resolves and normal activity is possible.
These notes were generated by AI and may contain inaccuracies.
The lymphatic system is a critical component of recovery that is often overlooked. All approaches to lymphatic support can be beneficial including manual lymphatic drainage, the Perrin technique, vibrational trainers, and homeopathic lymphatic drainage tools. Different parts of the lymphatic system require different methods to access them effectively. Lymphatic vessels in the back of the nasopharynx are extremely hard to access, as are the deep cervical lymph nodes and occipital lymph nodes, which are responsible for intracranial pressure and form a key part of recovery when supporting energy systems and immune function.
The expectation during recovery is that debris from ongoing immune battles will be generated as passengers acquired during immune dysfunction are addressed. This debris can cause lymphatic blockage leading to compartmentalized metabolism alterations, pressure, hypoxia, and other complications. The lymphatic system is not just a sewage system but also part of the fat delivery system from the diet and is involved in the ongoing immune response.
The lymphatic system lacks a pump unlike the cardiovascular system, requiring manual therapy to keep lymph flowing and prevent buildup and new bottlenecks. When lymphatic vessels are blocked there is a direct inhibition function on the immune system. Lymphatic support is started before repletion begins so that repletion does not create a new bottleneck. Lymph nodes that become blocked provide clues to localized infections, as they are adjacent to infected tissues. Nose and throat infections are likely to have face and neck lymphatic vessels blocked, while GI or gynecological issues are likely to have blocked lymph nodes around the groin. Throat and lung issues produce blockages around the armpits and chest.
Cortisol represents the slower increase toward adrenergic signaling compared to the rapid spikes of adrenaline and noradrenaline. Cortisol rises and falls slowly across the day in response to various signals including daily circadian signaling and metabolic problems. A branch from the glycolysis pathway regulates downstream pathways via a sensor relay called phosphated glycerine which controls corticotropin releasing hormone metabolism and adjusts between anabolic and catabolic hormonal states. This sensor detects glycogen levels, NAD redox status, P5P, and TCA cycle status through three phosphoglycerate going through a dehydrogenase for NAD redox, a transamination for P5P and TCA cycle status, and ultimately ending up as serine or phosphoglycerine.
Complex PTSD and childhood trauma are pervasive throughout the spectrum of people experiencing these conditions. If the nervous system never learned to regulate in childhood through co-regulation with parents and never learned that things will be okay after adversity, there is no safety signal to reach during metabolic dysfunction. For neurodivergent individuals who can hold fixations for extended periods, this fixation can become part of the disease process, focusing on the disease rather than recovery outcomes.
Figures 17, 18, and 19 describe the cascade of chronic nervous system dysregulation. Complex PTSD is a key focus, along with metabolic dysfunction from induced malnutrition and heavy metal buildup. Sleep deprivation triggers loss of fear extinction during sleep. Opioid metabolism dysregulation occurs downstream into microbiome adaptation to sympathetic overdrive, with the system winding up progressively toward hyperarousal and hypervigilance.
Mineral deficiencies and heavy metal buildup lead to dysfunctions around glutamate metabolism and calcium channel metabolism. Substance P is involved in calcium channel dysregulation from sympathetic overdrive. The array of symptoms including inflammation and pain means the nervous system, autonomic nervous system, and amygdala perceive threats from moving, breathing, eating, and sleeping with no safe place to retreat. Progressive sympathetic dominance occurs particularly when glycogen metabolism and parasympathetic signaling are lost.
Nasal dysbiosis, inflammation, mouth breathing, and sleep problems eliminate original parasympathetic signaling. Poorly maintained glycogen means no parasympathetic state to lean on. Energy for movement comes from increased sympathetic signaling and systemic energy metabolism including lipolysis and beta oxidation. POTS and orthostatic intolerance require energy to activate core muscles and balance when upright, which ramps up sympathetic pathways when localized glycogen storage is unavailable, leading to heart rate elevation.
Vagal tone management is helpful providing the metabolism underneath supports it. Shifting rapidly from sympathetic bias through interventions like stellate ganglion block without supporting metabolism leads to becoming massively hypometabolic and crashing. A period is required to eat and restore nutrients including glycogen itself and all co-factors required for the pathway.
Magnesium and phosphate are required for the top path of glycolysis and glycogen synthesis. Chromium and vanadium support glucose transporters and insulin response. The oxidative pentose phosphate pathway requires minerals including zinc for glutathione metabolism, glycine, and cysteine synthesis from methylation and transsulfuration pathways. Heavy metal buildup creates problems in these pathways. Thyroid signaling problems impair hepatic gluconeogenesis, reducing glucose sent from the liver from any substrates to feed muscles, brain, and glycogen stores.
When the liver cannot fill gaps in blood glucose, hypoglycemia episodes especially around meal times become problematic. Brain and muscle glycogen become progressively harder to maintain, making alarm states worse. As sympathetic overdrive progresses, the inability to swallow develops along with pharyngeal contraction and GI motility shutdown. The deeper into the sympathetic hole, the harder it becomes to swallow and digest food. Recovery requires shifting away from sympathetic bias toward a balanced parasympathetic to sympathetic state.
Being able to heal requires letting go of the story of illness, as being stuck in the trauma of illness drives sympathetic dominance. The disease model describes blind spots in the immune system where microorganisms hide or shield themselves within biofilms in many body locations.
Biofilms are created by microorganisms as part of their normal life cycle. They have a motile stage with flagella allowing them to swim and find new surfaces. Once finding a surface, they lose their flagella and create a biofilm around them like a cocoon protecting from insults. They transition from mobile single cell organisms to factories sitting inside protected cocoons taking metabolites in and producing metabolites, some potentially toxic. When they progress far enough they proliferate, come out of the biofilm, find new surface areas, lose flagella, and repeat the process.
The immune system does not have a good sense of what is inside biofilms and treats biofilms as largely inert substances without attacking them. Little factories progress over tissues including GI tract mucosal tissue and cardiovascular system as atherosclerosis. The immune system has no awareness of biofilm contents but can arrest microbes when they emerge from biofilms as a checkpoint, preventing progression of existing biofilms until the immune system is distracted with other threats.
When the immune system is busy with influenza or other co-infections, biofilms get opportunity to expand surface area. The immune system handles single threats well in acute situations and manages co-infections reasonably but struggles overall. The innate immune response has certain capabilities with a logical gate via JAK-STAT. Biofilm expansion over time, whether long or short depending on immune system state and host signaling, increases metabolites produced by microorganisms.
Studies in mice showed input to the hypothalamus caused the gut microbiome to retile within hours of nervous system shift without any food input, indicating signaling between host and microbiome. This signaling likely extends beyond gut microbiome to microbes in lungs, scalp, nasopharynx, sex organs, mucosal tissues, kidneys, and other places, causing microbes to receive signals and proliferate thinking they are doing something normal and helpful.
In sympathetic overdrive, the pathway starts at catecholamines including noradrenaline and adrenaline. Downstream of adrenaline goes through the cAMP and PKA pathway regulating energy systems and many other processes. The body produces opioids to downregulate the cAMP pathway. The microbiome creates fermentation syndrome through alcohol to acetaldehyde, largely acetaldehyde entering the system and altering NAD redox in the brain. This allows dopamine and DOPAL or dopamine and acetaldehyde to react forming salsolinol and a cascade of opioid alkaloids through to morphine. Endogenous pathways exist for morphine, codeine, and everything in that pathway, creating balance against elevated cAMP-PKA.
This maladaptive response leads to barrier dysfunction, histamine dysregulation in mast cell activation syndrome, mineral deficiencies, LPS getting through the barrier causing neuroimmune and neuroinflammation problems. When the immune system is distracted with external environment such as mold illness, microbial control decreases resulting in biofilm expansion.
There is interplay between lytic viruses and mitochondrial dysfunction leading to lactic acid metabolism and lowered lactate threshold. When the cell senses prolyl hydroxylases get inhibited, this allows hypoxia inducible factor 1 alpha to stabilize, triggering transcription factor alterations. Lactate dehydrogenase is promoted and pyruvate dehydrogenase kinase is promoted, creating the glycolytic shift. This also triggers lytic reactivation of various herpes viruses, creating additional chronic threats and distraction from other microbes.
Hypoxia connects to hypercoagulation and fibrin accumulation, which overlaps with biofilm formation and has worsened with spike proteins. Hypoxia in complex chronic illness can be driven by infection, immune activation, and other factors. Hypoxia inducible factor 1 alpha and succinate enter the discussion as key elements. Addressing the low oxygen state requires caution about introducing oxygen into the gut microbiome, which prefers a low-oxygen environment.
Oxygen transport issues extend beyond fibrin amyloid situations. Pre-COVID fibrin amyloid problems typically appeared in late-stage diabetes or immunocompromised states. Post-COVID and ongoing COVID cases show massive increases in fibrin amyloid issues, shifting from micro to macro scale with reports from embalmers and morticians.
Additional factors affecting oxygen delivery include vascular dysfunction linked to nitric oxide synthase. Nitric oxide synthase sits within the urea cycle and generates nitric oxide while participating in the immune response by generating superoxides during interferon signaling upregulation. NADPH oxidase also participates in the innate immune response.
BH4 alters nitric oxide synthase metabolism, determining coupled versus uncoupled NOS. Uncoupled NOS creates peroxynitrites, leading to mitochondrial dysfunction that shuts down complex one and complex three. Histidine and histamine dysregulation affects hemoglobin and oxygen transport. Oxidative stress and hyperammonemia further impact oxygen transport. Circulating parasites, bacteria such as Lyme and co-infections like Bartonella and Babesia, and chronic immune activation compound these issues when reactive oxygen and nitrogen species cannot be processed adequately.
Mineral deficiencies and heavy metal buildup impair metalloenzymes including Cu/Zn SOD, Mn SOD, catalase, glutathione peroxidase, and glutathione reductase. These enzymes normally manage reactive oxygen species and reactive nitrogen species. When metalloenzymes cannot perform, oxidative and nitrosative stress increases, producing oxygen transport issues, cardiovascular problems, and barrier dysfunction that allows circulating biofilms from species such as P. gingivalis, strep, and staph inside the cardiovascular system.
Blood-brain barrier and other barrier inflammation adds further impact. Structural issues arise when vascular Ehlers-Danlos syndrome or hypermobile Ehlers-Danlos syndrome metabolism persists long-term, potentially causing chronic cranial instability and impaired brain blood flow. The central nervous system then receives a hypoxia alarm signal.
An 80 percent reduction in upright versus supine blood flow has been observed via Doppler in some patients. All these factors create a tighter spiral into severe ME/CFS, long COVID, or vaccine injury regardless of the initial catalyst, resulting in multi-system progressive failure.
Supporting the nitrate-to-nitrite-to-nitric-oxide pathway versus the arginine-citrulline pathway carries different risks. Arginine may activate herpetic viruses. Nitric oxide supplementation can support endothelial NOS appropriately or overstimulate iNOS, moving in the wrong direction depending on context.
The risk of arginine or increased urea cycle flux comes from anaplerosis to fumarate. In the presence of hypoxia inducible factors that trigger viral reactivation, increasing fumarate or succinate inhibits prolyl hydroxylases, stabilizing HIF-1 alpha and leading to viral reactivation. Supporting the first half of the TCA cycle with magnesium, iron, sulfur status, fatty acid oxidation transport, and glycolysis may mitigate this concern.
Nitric oxide synthase requires multiple cofactors including calcium channel metabolism, riboflavin in two forms, and NADPH. It is upregulated during the innate immune response. NAD to NADPH regulation during complex one inhibition and interferon signaling shifts nitric oxide synthase metabolism. Dietary nitrates such as beetroot may be safer in some contexts, but if nitric oxide synthase continues generating superoxide and peroxynitrites the underlying problem persists. Nitric oxide synthase output also feeds back into the arginine-citrulline cycle, increasing overall flux.
Connective tissue disorders appear across the entire population with this metabolic model. The model predicts that connective tissue disorders occur simultaneously with metabolic dysfunction causing prolyl hydroxylase inhibition. Deeper mitochondrial dysfunction correlates with deeper connective tissue compromise. Correcting mitochondrial dysfunction enables progressive connective tissue repair when combined with structured stimulation.
Tissue rehabilitation requires mobility work and structured physiotherapy once metabolism supports it. Attempting rehabilitation during mitochondrial dysfunction can cause tears and progression to worse states. A free posture course linked in the protocol is available. Practitioners must understand EDS complexities, as those unfamiliar with the condition have caused deterioration.
Reactive oxygen species generation is normal in metabolism and the innate immune response. Normal mitochondrial metabolism generates reactive oxygen species, with glutathione metabolism acting as an automatic cooling system. Glutathione peroxidase and glutathione reductase ramp up in response to complex one inhibition. During induced malnutrition and heavy metal buildup this intersection becomes inhibited, so normal metabolism produces oxidative stress.
Reducing heavy metal burden and restoring metalloproteins improves cellular capacity to handle reactive species and normal metabolism. Dietary antioxidants including ascorbic acid, tocotrienols, and tocopherols help restore balance. Once metalloproteins are restored and heavy metals removed, resilience against normal metabolism and innate immune responses returns. Initial support is needed until the system becomes self-sustaining.
Hydrogen water shows some benefit for reducing oxidative burden, though it is not considered the most impactful intervention. Acidity and pH regulation also influence mitochondrial metabolism.
Post-exertional malaise involves glycogen insufficiency partly from dietary complexity and from glutathione metabolism impairment. Glutathione metabolism provides both mitochondrial cooling and the NADP redox. Oxidized glutathione is converted to reduced glutathione by glutathione reductase using NADPH, producing NADP. Enzymes in the oxidative pentose phosphate pathway including G6PD and 6PG convert NADP back to NADPH.
Insufficient redox partner activity bottlenecks oxidative pentose phosphate pathway flux, impairing production of PRPP and R1P needed for purines, pyrimidines, and NAD. UTP production is reduced, affecting UGPASE in glycogen synthesis and glycocalyx assembly via UDP-glucose. Cells cannot respond adequately to serum glucose increases.
Oxidative stress from heavy metal buildup, low zinc, and methylation/transsulfuration impairments blocks the oxidative pentose phosphate pathway, impairing glycogen synthesis. This creates a spiral of insufficient liver glycogen leading to brain and muscle glycogen deficiency. Sympathetic overdrive increases as glycogen drops, yet insulin sensitivity remains inhibited, preventing effective glycogen restoration.
Small frequent meals of 10-15 grams net carbohydrates hourly, similar to diabetes or metabolic syndrome management, help slowly restore glycogen stores without excessive inflammation. Supporting glutathione metabolism and oxidative stress improves insulin sensitivity, allowing more carbohydrate conversion to glycogen and entry into a functional TCA cycle.
The methylation-glutathione-oxidative pentose phosphate pathway axis is central. Correcting this axis reduces post-exertional malaise, POTS, and related symptoms.
Graded exercise is contraindicated for patients with measurable mitochondrial dysfunction from chronic infections, dysbiosis, and induced malnutrition. The body rewards appropriate movement, but appropriate levels vary widely between individuals. Continuous lactate meters would help measurement, but signals can be interpreted through lactate increase, hypoxaluria, muscle or brain lactate sensation, and liver pain.
Stagnation causes progressive deterioration. Minimal movement such as toe flexion, foot pumps, and hand squeezes may be appropriate for some, while others can manage short walks. The goal is to avoid depleting glycogen reserves by favoring low-impact steady-state cardio and fatty acid oxidation from lipolysis. High-intensity efforts and hill or stair walking should be avoided. Burst energy should stay under 8-10 seconds with 30-60 seconds recovery to utilize the ATP-PC pathway. Creatine supports this pathway.
The ATP-PC pathway can be leveraged for short bursts of energy, ideally kept under 8 to 10 seconds, with creatine being particularly helpful in this system. This approach allows stacking gains while working on recovery by staying out of a low glycogen state and avoiding oxidative stress. Finding personal energy envelope limits is essential, and progressive recovery occurred over roughly two years by keeping the nervous system calm, maintaining nutrition, and gradually building capacity. Eating only once per day during early recovery was later recognized as a factor that delayed progress.
Walking is highly underrated for its benefits. Even modest movement supports lymphatic flow and fluid dynamics. Four miles per day is a current target, though individuals should never exceed their current capacity, such as walking only to the mailbox if that is the limit.
NAD+ (oxidized), NADH (reduced), and NADPH are key redox currencies. ATP is foundational for synthesizing these molecules, including NAD and FAD pathways. Magnesium is typically required as MgATP, with ZnATP or CoATP also relevant in certain contexts such as riboflavin and P5P metabolism.
The TCA cycle generates NADH and FADH2, feeding electrons into the electron transport chain for efficient ATP production via ATP synthase. Glycolysis serves as the primary cytosolic ATP source but consumes ATP in its first half before generating it in the second half. Zinc deficiency inhibits glycolysis midway, so correcting zinc status is required to restore glycolytic ATP synthesis, which then supports downstream NAD, NADP, and other pathways. NAD kinase requires MgATP to convert NAD into NADP.
A controlled level of reactive oxygen species and complex I inhibition normally supports NADPH generation, which the body uses for hormone synthesis, tissue synthesis, and methylation. The body rewards modest oxidative stress with these benefits. However, chronically elevated NADH pools correlate with high testosterone or DHT levels before metabolic collapse occurs, indicating underlying zinc deficiency and mitochondrial dysfunction despite apparently favorable hormone numbers.
NADPH functions as a synthesis and immune-related molecule involved in NADPH oxidase activity, nitric oxide synthase activity, and hormone synthesis. ATP generation remains the foundational step that activates these downstream pathways.
Disregulated oxidative pentose phosphate pathway activity is linked to low inosine levels. Extracellular ATP acts as a danger signal triggering neighboring cells into alarm states and propagating mass cell activation and immune dysregulation. A low dose of inosine was added to the protocol to gate extracellular purinergic signaling, preventing low-level signals from escalating into amplified threat responses.
The cell danger response itself is a normal response to tissue damage but can become disregulated. The methylation-glutathione-oxidative PPP axis, along with NADPH generation and NOS/NOX activity, helps regulate this process. Early-stage support includes calming innate immune responses and extracellular ATP signaling.
Low-dose spirulina, schisandra, and low-dose curcumin are used as NOX inhibitors. Dextromethorphan (DXM) in cough syrup also inhibits NOX activity and oxidative stress generation, though it is not part of the current protocol. Breaking the cycle of oxidative stress and glycogen insufficiency helps reduce these spirals.
Key cytokines including TNF-alpha, IL-6, IL-1 beta, IL-10, and IL-22 alter levels of the peptide hormone hepcidin. Elevated hepcidin inhibits divalent metal transporter 1 and ferroportin, affecting mineral transport. Hormones, minerals, and vitamin D also influence hepcidin expression. Vitamin D's anti-inflammatory effects partly stem from normalizing mineral transport metabolism.
Normal inflammation supports tissue adaptation and immune responses, but excessive inflammation driven by malnutrition or metabolic disruption is counterproductive. Supporting mitochondrial metabolism and preventing excessive lactate shift reduces cytokine elevations that further disrupt mineral transporters. Sleep quality also directly affects TNF-alpha, IL-6, and IL-1 beta levels.
Heavy metals impair glutathione and TCA cycle function. Figure 12 illustrates how normal inflammatory pulses of hepcidin sequester minerals and metals into brain, liver, kidneys, and spleen. When glutathione metabolism is impaired, these metals accumulate, creating a self-reinforcing spiral. Restoring mineral repletion and removing accumulated heavy metals is central to reducing inflammation.
No melatonin is included in the protocol. It can be used successfully and supports glymphatic clearance of toxins from the brain during cellular maintenance processes, including exosome export. Regulatory barriers exist in some countries, including Australia, where even nutritional-dose lithium is restricted. A recent study suggested potential cardiovascular concerns with exogenous doses, though data do not indicate melatonin is inherently harmful. It should not be relied upon in isolation for recovery.
Extracellular glutamate stimulates activity while intracellular glutamate drives glutathione synthesis. Glutathione dysregulation, combined with sympathetic overdrive affecting cAMP and protein kinase A, contributes to elevated extracellular glutamate. Low magnesium, zinc, P5P, and GAD activity reduce GABA production, worsening the imbalance.
Glutamatergic dysregulation appears across ME/CFS, long COVID, POTS, ADHD, autism, and PTSD, reflecting shared metabolic and autonomic nervous system roots. Correcting the core methylation-glutathione-oxidative PPP axis and restoring glycogen metabolism is expected to normalize glutamate-GABA balance.
Histamine supports barrier defense responses and post-exercise glycogen distribution from liver to muscles. Histamine is metabolized via monoamine or diamine oxidase followed by aldehyde dehydrogenase. Mitochondrial complex I dysfunction and NAD redox issues impair aldehyde dehydrogenase, causing aldehyde metabolite accumulation downstream of histamine.
Barrier dysfunction from mitochondrial issues and pathogens allows foreign proteins to trigger histamine release while degradation pathways are simultaneously compromised, leading to mast cell activation syndrome patterns. Cell danger response and extracellular ATP signaling can trigger mast cell degranulation independently of foreign proteins. Nervous system threat perception alone, demonstrated in virtual reality studies, is sufficient to initiate this cascade.
When histamine degradation is impaired, elevated histamine interacts with dopamine metabolism in cell-specific ways, further disrupting brain function. The goal is restoring homeostasis by removing external triggers, repairing degradation pathways, and correcting nervous system drivers of inappropriate histamine release.
Limbic system retraining, vagal tonification, and autonomic nervous system regulation produce measurable physical effects on mast cell stability and histamine tolerance by addressing sympathetic dominance.
Working on lyic system retraining, vagal tonification, and nervous system support helps stabilize mast cells and reduce histamine intolerance. As the discussion moves into the protocol, the pathway diagrams can feel overwhelming, raising the question of whether every aspect needs direct assessment and support or if providing the right inputs like minerals and removing contributors such as metals, infections, and biofilms allows pathways to self-correct toward homeostasis.
Focusing too heavily on the disease process creates more dysregulation. Micromanaging and attempting to correct every detail contributes to homeostasis disruption rather than supporting recovery. The goal is to restore minerals and resources, remove heavy metals, and progressively return to a normal diet and lifestyle while staying out of the body's way as it recovers.
The idea is to restore the minerals, restore the resources that are there, pull the heavy metals out and essentially get back to, you know, as much as you can progressively a normal diet and normal lifestyle and stay out of the way of the body actually recovering.
This approach presents a paradox: attempting recovery while the brain remains fixated on illness. The recommendation is to show the body kindness by restoring metabolism toward homeostasis, allowing the nervous system to reset and stop perceiving threats. In severe stages, everything appears threatening, hope diminishes, and fear of making wrong decisions that worsen the baseline becomes constant.
Online groups often reinforce doom and gloom narratives focused on what cannot be done, which harms mental states and recovery beliefs. The medical community bears responsibility for allowing this state to persist by not better understanding and treating these conditions, leaving patients without adequate support.
The body possesses innate intelligence and wisdom. Attempts to control it, often driven by ego or fear, move in the wrong direction rather than trusting the body's own design.
The protocol consists of three main stages:
- Stage 1: Remineralization, increasing collagen synthesis, and performing a controlled initial die-off.
- Stage 2: Enhancing gastrointestinal and mucosal interventions, including targeted and untargeted antimicrobial supports.
- Stage 3: Stimulating and supporting a strong immune response to clear remaining reservoirs after foundational work is complete.
The protocol is not strictly the same list for everyone. Customization draws from OAT tests, Oligo Scan results, and other data. Sensitive individuals can stretch stages and introduce interventions more slowly to minimize Herxheimer or detox reactions. Stage 3 should not be approached until basics are addressed and near-normal life is achieved. It is not strictly required to break out of the initial illness state, which is largely handled in Stages 1 and 2.
Stage 1 centers on repletion: restoring cellular resources, removing heavy metal and microtoxin burdens, and restoring glutathione metabolism, methylation, and glycogen stores. As energy metabolism improves, immune cells wake up and begin addressing accumulated invaders. Care must be taken to support this process to avoid creating unsustainable burdens, maintaining glycogen and managing oxidative stress during the initial immune response.
Stage 2 incorporates broad-spectrum products such as GI Synergy (antiparasitic and antimicrobial) as a catch-all, though ingredients like berberine require caution. Berberine acts as a complex I inhibitor and ramps up CD36 fatty acid transport; without sufficient oxidative stress correction and carnitine synthesis support, it can promote fatty liver-type metabolism. Targeted interventions become available when good data from MicroGenDX or similar testing identifies specific pathogens.
Traditional antibiotics risk broad elimination of beneficial species. Bacteria phages, more advanced in Russia and surrounding countries, offer selective targeting without prescription, infecting and replicating within susceptible strains like specific E. coli variants in a chain reaction until resistance develops.
Sympathetic overdrive contributes to overgrowth of fermenting species. Until this is addressed, overgrowth of fermentation syndrome-related organisms is likely to persist. Mucin and butyrate issues must also be resolved to support regrowth of lactic acid bacteria, Lactobacillus, and Bifidobacterium. Probiotics alone will not colonize without proper diet and terrain support. The process of correcting host factors begins in Stage 1 and progresses into Stage 2, where removal of problematic species becomes easier as sympathetic signaling balances toward parasympathetic dominance.
Stage 3 clears remaining pathogen reservoirs in tissues after foundational recovery. This step prevents future gut issues, random infections, and other problems from "sleeper cells" that could return later. One personal example involved post-recovery GI sensitivities and gluten issues that resolved only after addressing specific remaining problems following a motorcycle accident and hospital antibiotics.
Progression is tolerance-related. Severe cases require gentler pacing to show the body kindness and restore cellular metabolism and nervous system balance without aggressive intervention. Certain elements, such as calcium, require titration for those with calcium channel dysregulation or glutamate issues. Autoimmune antibodies can serve as targeting assessments; as underlying metabolism is restored, these antibodies often disappear without direct targeting.
For patients intolerant of many supplements, addressing limbic, vagal, and sympathetic dominance first improves tolerance of other tools.
Die-off and Herxheimer reactions relate to pathogens accumulated during immune sluggishness. Immune activity, feeling sick, and Herx-type reactions are expected as energy metabolism improves. Inflammation blocks normal absorption, creating a cycle where low minerals or high burdens sustain inflammation. The protocol bypasses duodenal transporters using sublingual, troche, liposomal, and DMSO-based routes.
Magnesium forms have shifted toward magnesium glycerophosphate, which may drop into the glycolysis pathway after the PFK1/2 bottleneck. Sublingual administration shows promise, though oral absorption questions remain from pediatric IV studies. Calcium channel dysregulation can impair GI magnesium uptake via channels such as TRPM7.
Peripheral nervous system reactivity to pH changes, plant compounds, or even fizzy water can trigger central nervous system alarm cascades. Calming sympathetic signaling with interventions like inosine supports CDR and reduces reactivity, enabling safer supplement introduction through gradual exposure therapy.
Transdermal magnesium delivery can be more successful than oral routes in some cases. Epsom salt foot baths or baths provide one option. For those using the toapole protocol, a magnesium spray or gel can help get magnesium into the system via a different route until things settle down and oral intake becomes easier.
Many people, particularly those with lymphatic system impairment, are concerned about citric acid. The rationale for including it involves multiple factors. Citric acid helps dissolve oxalate and excrete it, which is a significant problem for many people. Hypoxillura increases progressively with lactic acid metabolism, so the deeper the metabolic impairment, the more oxalate problems are expected.
Citric acid is also useful for biofilm in the upper GI tract. Many people suffer from reflux and GERD partly from zinc deficiency, but also because biofilm in the upper GI produces gases that inflame the esophageal sphincter and pyloric sphincter. Dealing with biofilm in the upper GI reduces these problems and decreases reactivity to simple sugars, fruit juice, and similar foods that feed microbes in the upper GI. Complex carbohydrates are digested further down the tract.
Citric acid triggers some histamine response when breaking biofilms and exposing immune surveillance to microbial contents. However, starting with tiny doses and titrating slowly allows the body to build resilience. Avoidance is not the path to progress; finding a tolerable dose and moving forward slowly is the goal.
Stages one, two, and three include probiotics for microbiome support through a process of clean slate, reseeding, feeding, and then maintenance and monitoring. The metabolic daily product contains clostridium butyricum for butyrate production along with akkermansia.
Some chronically ill people already have high akkermansia levels, which can be detrimental to the mucin layer. The elevation often appears in people with very narrow processed food diets where the microbiome is attempting to compensate. If akkermansia levels are already high, additional supplementation is not necessarily needed. The amount of akkermansia in the probiotic is relatively small.
Compounded nutrients are adjustable based on data. Iron requires particular attention: if transferrin saturation is 40 or higher, iron may already be accumulating and adding more is inadvisable. The body regulates minerals effectively and excretes excess at nutritional doses. The Jason Hommel copper evolution protocol demonstrates this, with participants excreting large amounts of copper when taking up to 100 milligrams daily.
The goal is to avoid toxicity while staying within reasonable boundaries. If data shows specific deficiencies in zinc, copper, manganese, and cobalt, there is no need to take other minerals that are already adequate. For those in a chronic inflammatory cycle with suboptimal diet, broader mineral support may still be beneficial.
Electrolyte intakes are adjusted based on dietary inputs to reach total daily repletion targets, generally around daily values. Regulatory bodies recommend approximately 5 grams of elemental potassium daily, though many people fall far short. Potassium pills are limited to 99 milligrams because they are enteric coated and can cause irritation when absorbed in the wrong GI location. Consuming potassium as a salt in foods allows absorption in a different part of the tract with less irritation.
The sipper recipe is adjusted using an electrolyte calculator tool on the website. If dietary intake provides 3 grams of potassium, only 2 additional grams are needed from the sipper.
B vitamins exist in multiple forms. Dietary intake typically provides inactive forms that require conversion via metalloenzymes. When mineral deficiencies impair these conversions, supplementing active forms helps restore metabolism faster.
For B1, TPP (thiamine pyrophosphate) is used. Thiamine itself binds to acetaldehyde as an adduct, reducing available thiamine. Benfotiamine is fat-soluble and may have a better chance of conversion to TPP via TPK1, but direct access to TPP allows bypassing those steps.
For B2, R5P (riboflavin 5 phosphate, also called FMN) is used. FAD is not available supplementally. For B3, NAD is used directly via sublingual route at approximately 40-50 milligrams a few times daily, bypassing the gut and various conversion bottlenecks. This is particularly important when fermentation syndrome, excessive CMP, PK downregulation, or low zinc impair conversion of NMN or NR to NAD.
Even with NAD supplementation, redox balance between NAD and NADH can remain problematic. One case showed NAD 50% above normal while NADH was 250% above normal, with the NADP/NADPH pool very low at negative 500-600%. Active forms and non-oral routes yield more efficient therapeutic response while metabolism is impaired. As minerals are restored and heavy metals removed, the requirement for active forms decreases.
Multiple phosphate-containing compounds do not pose significant risk at the doses used. Acidity is a minor consideration. Doses are in the milligram range compared to gram-level electrolyte targets. Twenty milligrams of TPP, for example, yields only a small fraction as actual thiamine since the pyrophosphate comprises roughly two-thirds of the compound.
Uridine is included primarily for glycogen synthesis support. Uridine monophosphate sidesteps the oxidative pentose phosphate pathway bottleneck, moving through two steps to regulate UGPP activity. This supports glycogen synthesis while NAD redox and the oxidative pentose phosphate pathway remain inhibited. It also supports phospholipids and dopamine metabolism.
Good State ionic minerals are used in both men and women. Dosing starts at one drop and builds slowly to the recommended 4-5 milliliters, increasing further in stage three. The fulvic acid component aids detoxification, biofilm breaking, and mineral transport during inflammation. Starting at one drop is essential because it can dramatically shift metabolism and trigger strong immune responses. It should not be introduced until PEM issues resolve and normal activity is possible.
Biofilm Phase 2 Advanced is cycled 4 days on, 3 days off. Additional biofilm tools include NAC, glutathione, alpha-lipoic acid, and EDTA. Antifungal support begins with undecylenic acid.
When microorganisms die, cell wall rupture releases internal toxic compounds that create a wave of toxins requiring metabolism. This can occur in the microbiome or circulate to the liver. Clearing acetaldehyde production may also decrease endogenous opioid synthesis, producing opioid tolerance or withdrawal symptoms. The protocol specifically addresses this possibility with management steps.
Stage two includes candida support and interventions for common pathogens. A table in the living without chronic dysbiosis section provides targeted interventions based on species data, along with binder recommendations to reduce host metabolic impact.
Reishi complex supports immune function in stage three. The Life Extension Reishi extract was selected after extensive comparison for its specific compound profile. Reishi alters mitochondrial metabolism to favor immune response and unlock certain immune activity problems. It is used in combination with beta glucans to stimulate NK cell proliferation while signaling via reishi to upregulate the immune response.
Inosine dosing also increases in stage three.
In stage three, inosine dosing increases significantly from small amounts used for CDR support in earlier stages to 250-500 mg. This escalation aims to promote a robust immune response once the immune system and mitochondrial metabolism can effectively handle threats. Starting this process before achieving functioning energy metabolism can lead to negative outcomes.
Stage three includes explicit warnings against beginning without meeting specific criteria. Persistent mineral deficiencies, low phosphate and sulfur levels on oligoscan results, or ongoing PM all serve as gates that prevent progression. These indicators signal that energy metabolism is not yet ready to support the demands of stage three.
Binders discussed include Enterosgel, zeolite, bentonite, and diosmectite. These compounds already bind heavy metals and remain fairly inert in that context. Exposure to substances like fluoride and aluminum from sources such as tea differs when the metals exist in free ion form versus already bound to a binder.
Nano versions of binders raise separate concerns. Nano minerals, nano metals, and nano particles lack sufficient study, making their safety profile unclear. The protocol generally advises avoiding nano formulations for this reason.
Bentonite and charcoal function as broad-spectrum binders that capture virtually everything, including nutrients and medications. This broad action limits their use when nutrient absorption or medication timing matters. Narrower binders such as Enterosgel or Silicol gel primarily target acetaldehyde and selected compounds without significantly depleting nutrients or interfering with drugs.
Enterosgel and Silicol gel are generally well tolerated and carry lower risk of complications. Broad binders like bentonite and charcoal remain useful when timed carefully, typically at the beginning or end of the day to minimize interference with nutrient absorption.
The protocol is publicly available for anyone to read. Implementation ideally occurs under physician guidance, though the document explicitly states this recommendation in multiple places. The scarcity of trained clinicians has created access challenges, with existing practitioners now saturated.
A new institute is being established to provide single and group training for clinical teams. The goal is to build a complete ecosystem including clinician education, accreditation, and continuing education credits required by professional boards. Tools available on the Born Free website also exist in slightly modified form within the clinician toolkit for institute members.
Peer-to-peer consulting with clinicians treating complex disease patients helps bridge educational gaps regarding the model and disease processes. Long-term plans focus on institutionalizing the work to scale beyond individual capacity.
When implemented carefully and at tolerable rates, the protocol should not require avoiding nutrients or the removal of toxic metals. Intolerance to slow titration of minerals and co-enzymes suggests an underlying blocking factor. Possible blockers include nervous system dysregulation, downstream metabolic issues, or immune system responses to pathogens that produce intolerable symptoms such as increased intracranial pressure from inadequate lymphatic drainage.
Each case requires individualized assessment. Patients need sufficient comfort and trust in the guidance they receive, which depends on broader education across both patient and clinician communities.
The Collaborative Sciences Institute trains a wide range of practitioners including functional medicine doctors, GPs, neurologists, naturopaths, nutritionists, health coaches, and other modalities. The clinical care model incorporates frontline support through coaches, mentors, and patient advocates who handle day-to-day management under medical oversight, enabling lower-cost ongoing care.
Psychological support is integrated when needed. Trauma produces measurable biochemical changes; studies have shown altered immune function persisting a decade after single traumatic events such as bombings. The model addresses these effects holistically rather than treating the condition as purely psychological.
Simple diagrams in the protocol introduction illustrate a spiral process showing how patients may enter severe ME/CFS or similarly labeled conditions and the reverse sequence for recovery. Patient profiling identifies the "squeakiest wheel"—the primary blocking issue requiring initial focus, whether nervous system regulation, supplement tolerability, or other factors.
A suggested order of steps is provided in the spiral diagram, with each stage unlocking the next when performed carefully. One relevant observation from Dr. Neil Nathan states: "It's not psychological, it's neurological."
Daily practices include sufficient exercise, self-care, time outdoors ("touch grass"), and clean eating focused on a paleo-style approach with raw, organic, unprocessed foods. Consuming a rainbow of different organic foods is emphasized. Mental health maintenance involves addressing sources of trauma and grief. The guiding principle is to remain in a growth state rather than a decline state.
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