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The full base spike detoxification protocol is as follows:
Bromelain 500 mg once a day, nattokinase 2,000 FU twice a day, and curcumin 500 mg twice a day. The regimen is to be followed for 3-12 months or more, depending on disease resolution progress. These are initial dosages and may be adjusted in accordance with the tolerability and severity of injury syndrome. Because doses are far below known limits of safety, dose escalation would be reasonable if there are residual symptoms after three months of therapy. If ANA is positive and an autoimmune disease is suspected, prescribed hydroxychloroquine 200 mg twice a day should be added to the regimen. If pleurodynia or atypical chest pain is present, prescribed colchicine 0.6 mg once a day should be used in addition.
Nattokinase, a proteolytic enzyme derived from the fermentation of soybeans by Bacillus subtilis natto [44], has been traditionally used in Japan for cardiovascular benefits and possesses direct fibrinolytic activity by hydrolyzing fibrin and plasmin substrate, meaning it can be used to dissolve blood clots [45]. This makes nattokinase a vital tool to dissolve spike protein-induced blood clots, as they may contain fibrin that is resistant to fibrinolysis [19]. Additionally, nattokinase has a potent degrading effect on the spike protein of SARS-CoV-2 [46,47]. Figure 4 shows the degradative effect of nattokinase on spike protein on the cell surface [47]. The extensive persistence of spike protein [35,39,40] indicates that external drugs, specifically protein-degrading enzymes such as nattokinase, may be needed to degrade it in the human body. Kurosawa et al. demonstrated that, in humans, D-dimer levels were notably increased at both six and eight hours, while blood fibrin/fibrinogen breakdown products showed a significant rise four hours post the intake of a one-time oral dose of 2,000 FU (100 mg) (p < 0.05) [48]. Based on these findings, a suggested initial dosage might be 2,000 FU administered twice daily. Nattokinase has been shown to be largely safe other than possible excessive bleeding especially when combined with other medications [48].
(A) Degradative effect of nattokinase on spike protein on the cell surface. Spike-pcDNA3.1 was transfected with HEK293 cells and incubated for 9 h. After incubation, nattokinase (25 and 2.5 µg/mL) was added to the culture medium and further incubated for 13 h. Cells were fixed, and immunofluorescent analysis was performed. S protein on the cell surface was stained with an anti-spike protein antibody (red), and the nucleus was stained with DAPI (blue). (B) Ratio of the S protein area to the nucleus positive area. Three images per sample were captured, and S protein/nucleus positive areas were calculated. Data are shown as mean + SD, and the p-value was determined by one-way analysis of variance (ANOVA) with Tukey’s post-hoc test using R software (R-3.3.3 for Windows) (** p < 0.01; *** p < 0.001). (C) Cell viability was evaluated by an MTT assay. Indicated nattokinase was added to the culture medium and incubated for 13 h; an MTT assay was performed.
Bromelain, a proteolytic enzyme sourced from the stem of pineapples [49], has been traditionally hailed for its healing and anti-inflammatory capabilities, particularly in cases of arthritis and injury. Of significance is bromelain’s anticoagulant activity. It downregulates PGE-2 and thromboxane A2, promoting a relative prostacyclin abundance in platelets. Furthermore, it aids in fibrinolysis by promoting plasminogen conversion to plasmin and inhibiting platelet aggregation [50]. Kritis et al. demonstrated that bromelain can obstruct SARS-CoV-2’s entry into cells by cleaving its spike protein and reducing ACE2 and TMPRSS2 expression [51]. This enzyme can also hydrolyze glycosidic linkages, which comprise spike protein’s glycosidic shield that helps protect it from immune responses [52]. To attenuate inflammation, bromelain, in part, downregulates the pro-inflammatory prostaglandin E−2 (PGE-2) through inhibition of NF-kB and cyclooxygenase 2 and inhibits inflammatory mediators [51]. Thus, bromelain exerts multiple mechanisms of action against spike protein’s toxic effects and persistence. Bromelain has been used as a daily dosage of 200-2,000 mg; thus, 500 mg is a suggested initial dose [53]. Bromelain is mainly safe with low toxicity, but it can amplify bleeding risk and affect the absorption rate of several medications, potentially leading to drug interactions [54].
Curcumin, a polyphenol extracted from turmeric, is renowned for its anti-inflammatory properties and its ability to modulate inflammation during viral infections. Curcumin also supports fibrinolysis and the process of anticoagulation [51]. Beyond its traditionally recognized benefits, curcumin has shown promising antiviral actions against a wide range of viruses, including influenza, hepatitis, and notably, SARS-CoV-2 [55]. It achieves this by obstructing the spike protein’s binding sites (ACE2 receptors and TMPRSS-2). Curcumin’s anti-inflammatory effects are realized through inhibiting NF-κB signaling [56]. An in-silico study found that curcumin can inhibit the spike protein of the Omicron variant through interaction with its amino acids [57]. Randomized trials have consistently indicated decreases in high-sensitivity C-reactive protein (hs-CRP) and other markers of inflammation in situations involving spike protein-induced infections or injuries [58,59]. Curcumin is non-toxic at doses up to 8,000 mg a day [60]. Large doses, particularly with ill-absorbed formulations, can lead to gastric complications [61]. Enhanced absorption of curcumin is achieved in combination with piperine, or with nano or liposomal formulations, which are available as over-the-counter oral supplements. Doses vary widely depending on the formulation, but 500 mg twice a day has been shown to be a common and safe dosage regardless of curcumin type [61].
Hydroxychloroquine, a well-known FDA-approved antimalarial and anti-inflammatory, adds additional support for immunocompromised patients by inhibiting the binding of spike protein to human cells [62]. A real-time meta-analysis of 413 published peer-reviewed studies for hydroxychloroquine as a treatment for COVID-19, including a total of 529,687 patients, shows a statistically significant lower risk for mortality and hospitalization, along with accelerated viral clearance [63]. This effect was the strongest when patients were treated early, indicating the importance of early treatment. Since hydroxychloroquine accelerates viral clearance, it subsequently assists in spike protein removal, and it may be a great addition to base spike detoxification. This compound has been found to be well-tolerated, safe, and not associated with a risk of ventricular arrhythmia at a dose of 200 mg twice a day provided that the expected prolongation of QTc is managed along with other drugs with serial ECGs. Gastrointestinal symptoms may occur [64].
Colchicine, an FDA-approved alkaloid found in the plants Colchicum autumnale and Gloriosa superba, has been traditionally used in therapeutics for its anti-inflammatory properties [65]. This compound can reduce the risk of myocardial infarction and stroke [66]. Moreover, colchicine may reduce myocardial injury in the presence of spike protein [67]. Pleurodynia has been diagnosed post-COVID-19 vaccination and may be indicative of cardiac inflammation [68]. The COLCORONA trial demonstrated that colchicine was safe and had a favorable impact on COVID-19 and its immediate post-acute sequelae. In patients with PCR-confirmed COVID-19, colchicine lowered the rate of hospitalization and death compared to placebo [69]. A meta-analysis of five randomized trials, including a total of 16,048 patients, found that colchicine decreased COVID-19 severity and decreased C-reactive protein (CRP), indicating its potent anti-inflammatory effect in the presence of spike protein [70]. Thus, the addition of colchicine is indicated when a patient presents with pleurodynia post-COVID-19 vaccination or post-infection. Moreover, 0.5 mg twice daily has been shown to be a safe and effective dosage for the treatment of COVID-19 [65,69,70].
Additional compounds that may assist in spike protein detoxification and degradation include the following:
N-Acetylcysteine (NAC): It dissolves spike protein through the destruction of disulfide bonds and prevents binding at ACE2 [52,71,72].
Glutathione: It disrupts spike protein disulfide bonds [72].
Ivermectin: It binds and inhibits spike protein [73].
Quercetin: It binds and inhibits spike protein [74].
Apigenin: It binds and inhibits spike protein [74].
Nicotine: It disrupts glycosylation on spike protein and blocks possible spike protein-nicotinic cholinergic receptor interaction [75,76].
Emodin: It blocks the spike protein-ACE2 interaction [77].
Fisetin: It binds and inhibits spike protein [78].
Rutin: It binds and inhibits spike protein [79].
Silymarin: It binds and inhibits spike protein [80].
Discussion
We found abundant evidence that SARS-CoV-2 spike protein may cause biological damage in the cardiovascular, hematological, neurological, respiratory, gastrointestinal, and immunological systems [13-36]. Mechanistically, spike protein has been shown to cause dysfunction in many cell types by causing metabolic deteriorations, leading to cell death. Stabilized prefusion (vaccine-derived) spike protein may possess similar harmful mechanisms as viral spike protein. Spike protein is found, in the absence of nucleocapsid, directly in cardiomyocytes and blood clots in patients diagnosed with myocarditis and acute stroke, respectively [17,21]. Vaccine-derived and viral spike proteins have been found in humans for at least 6-15 months after vaccination or infection [35,39,40] in those with post-acute sequelae, indicating spike protein as a possible primary contributing factor to long COVID, with substantial persistence in human systems due to the absence of an innate clearing mechanism. However, more research is needed to further investigate the effect of spike protein in patients with post-acute sequelae after COVID-19 and COVID-19 vaccination. Meanwhile, the current data points to a strong signal to urgently develop spike protein detoxification protocols.
Although methods to degrade or block spike protein have been investigated [46,47,51,52,56,57,62,71-80], there are currently no widely accepted protocols to do this in human subjects. The McCullough protocol: base spike detoxification is the first protocol established to help remove spike protein derived from SARS-CoV-2 infection and vaccination in humans. The three-drug regimen of nattokinase, bromelain, and curcumin was chosen due to their proven safety records, as well as their anti-inflammatory and anti-coagulant properties combined with their synergistic and potent effects in degrading and inhibiting spike protein [44-61]. This protocol may be useful in the attenuation of COVID-19 vaccine-induced injury syndromes and long-term COVID-19 complications.
The addition of other agents that can further assist in the detoxification of spike protein [62-80] may be indicated based on clinical outcomes. Most notably, the addition of N-acetylcysteine (NAC) may add an extra mechanism of action against spike protein to the protocol. NAC has been shown to disrupt disulfide bonds of the spike protein, rendering it unable to bind to the ACE2 receptor [71,72]. Moreover, the combination of NAC with bromelain has been shown to synergistically disrupt spike protein by breaking glycosidic linkages and disulfide bonds [52]. NAC has a well-established safety profile and is commonly taken at a dose of 600 mg twice a day [81]. Thus, the addition of NAC to the regimen of bromelain, curcumin, and nattokinase may be useful for individuals with severe treatment-resistant COVID-19 or COVID-19 vaccine-related complications. Since all of these compounds can reduce blood clotting, patients should be counseled and monitored for bleeding complications, including easy bruising, nasal mucosal bleeding, and gastrointestinal hemorrhage. Self-administration is not advised without physician oversight.
The base spike detoxification protocol was devised based on the best evidence currently available. No therapeutic claims can be made until large-scale, prospective, randomized, double-blind, placebo-controlled trials are completed. On November 15, 2023, we searched clinicaltrials.gov and found no planned or ongoing trials with nattokinase or bromelain in the treatment of post-acute sequelae after COVID-19 or vaccination. However, there is a planned trial to assess the effect of curcumin, in conjunction with boswellia and vitamin C, on long COVID [82]. Thus, base spike detoxification is an important advancement in the development of testable hypotheses for future trials assessing treatments for SARS-CoV-2 infection and post-COVID-19 vaccination injury syndromes.
Conclusions
SARS-CoV-2 spike protein is a highly persistent, potentially pathogenic substance that may incite inflammation and tissue damage in almost all organ systems, resulting in post-acute sequelae. The vaccine-generated spike protein is different from the viral type, but both have been associated with deleterious effects and persistence in biological systems. Thus, therapeutics that target spike protein may be essential in treating COVID-19, its long-term effects, and possibly COVID-19 vaccine injury syndromes. Base spike detoxification is a promising proposal designed to theoretically attenuate spike protein and its associated damage. However, more pre-clinical and clinical research is needed culminating with large-scale, prospective, randomized, double-blind, placebo-controlled randomized trials to fully assess safety and efficacy. Moreover, further investigation is essential to ensure vaccine-produced, stabilized prefusion spike protein safety and half-life in humans and that it does not possess the same deleterious effects as the viral spike protein.
