The McCullough Protocol for Long COVID: What the Evidence Actually Shows

An evidence-aware academic review of the “base spike detoxification” regimen of nattokinase, bromelain, and curcumin

Yoon Hang Kim, MD, MPH | Board-Certified in Preventive Medicine | Integrative & Functional Medicine Physician

www.directintegrativecare.com

Abstract

Persistent symptoms after acute SARS-CoV-2 infection, commonly referred to as long COVID or post-acute sequelae of COVID-19 (PASC), continue to affect an estimated 65 million people worldwide (Davis et al., 2023). One proposed contributor is persistent viral antigen, including circulating spike protein, detectable in plasma months after acute infection (Swank et al., 2023). In 2023, Hulscher and colleagues published a clinical approach paper proposing a “base spike detoxification” (BSD) regimen — oral nattokinase, bromelain, and curcumin — informally known as the McCullough protocol (Hulscher et al., 2023). This article reviews the biological rationale, the available human evidence, and the safety considerations that clinicians should weigh before recommending the protocol to patients.

1. Background: Why “Clear the Spike”?

Long COVID is a heterogeneous post-viral syndrome with proposed mechanisms including viral persistence, immune dysregulation, microvascular injury, autoimmunity, and dysautonomia (Davis et al., 2023). One of the more compelling biological signals is the detection of circulating SARS-CoV-2 spike antigen in patients with PASC up to 12 months after acute infection, in contrast to fully recovered controls (Swank et al., 2023). Tissue-based studies have extended this observation, identifying viral RNA and protein in gut, lymphoid, and other tissues nearly two years post-infection (Davis et al., 2023; Swank et al., 2023).

These observations have catalyzed interest in two complementary therapeutic strategies: (a) antiviral approaches aimed at suppressing residual viral replication, and (b) interventions intended to neutralize, degrade, or clear circulating spike protein and mitigate its downstream effects on endothelium, coagulation, and innate immunity. The McCullough “base spike detoxification” protocol is one of several proposals in the second category.

2. The McCullough Protocol: What Is It?

In a 2023 paper published in Cureus, Hulscher, Procter, Wynn, and McCullough proposed a base spike detoxification regimen for patients with post-acute sequelae after SARS-CoV-2 infection or COVID-19 vaccination (Hulscher et al., 2023). The published regimen consists of:

• Nattokinase 2,000 FU (≈100 mg) orally twice daily, on an empty stomach
• Bromelain 500 mg orally once daily, on an empty stomach
• Curcumin 500 mg orally twice daily (nano, liposomal, or piperine-enhanced formulations preferred for absorption)

The authors recommend duration of 3 to 12 months or longer, individualized to symptom trajectory, and explicitly note that the regimen is empiric (Hulscher et al., 2023). Four putative mechanisms are proposed: proteolytic degradation of spike protein, inhibition of spike-mediated inflammation, dissolution of microthrombi, and attenuation of hypercoagulability (Hulscher et al., 2023).

3. Evidence Quality: A Critical Appraisal

It is essential to be precise about what kind of evidence supports the protocol. The Hulscher et al. (2023) paper is a clinical approach/hypothesis-generating article, not a clinical trial. The authors themselves write that “no therapeutic claims can be made for this regimen because it has not been tested in large, prospective, double-blind, placebo-controlled randomized trials” (Hulscher et al., 2023). To date, no such randomized trial validating the McCullough protocol for long COVID has been published.

The available evidence base can be summarized at three tiers:

3.1 Mechanistic and preclinical data

Each individual ingredient has plausible in vitro or animal data relevant to spike biology. Nattokinase is a fibrinolytic enzyme derived from Bacillus subtilis var. natto fermentation and has demonstrated fibrin-degrading activity in animal models and human cardiovascular studies (Chen et al., 2018; Li et al., 2023). Bromelain, a proteolytic mixture from Ananas comosus, has anti-inflammatory and antiplatelet effects in preclinical models. Curcumin modulates NF-κB and other inflammatory pathways in vitro (Hulscher et al., 2023). However, mechanism does not equal clinical efficacy in long COVID patients.

3.2 Indirect human data

A 2023 meta-analysis of six randomized controlled trials (n = 546) found that nattokinase supplementation modestly reduced systolic and diastolic blood pressure, supporting cardiovascular plausibility but not long COVID outcomes specifically (Li et al., 2023). Curcumin and bromelain have similar profiles: cardiovascular and anti-inflammatory signals in non-COVID populations, with no controlled long COVID outcome data.

3.3 Direct long COVID outcome data

At present, the published literature contains no adequately powered randomized controlled trial demonstrating that the McCullough protocol improves validated long COVID outcomes such as PROMIS fatigue scores, post-exertional malaise, orthostatic intolerance, or cognitive metrics. Independent fact-checking sources have similarly noted the absence of trial validation (Jaramillo, 2023). The protocol remains, by its authors’ own framing, an empiric clinical proposal.

4. Where the Protocol Sits in the Broader Long COVID Landscape

Current long COVID therapeutic research falls into three broad categories. First, antiviral programs such as the NIH RECOVER-VITAL platform are testing whether agents like nirmatrelvir/ritonavir can clear persistent viral reservoirs. Second, monoclonal antibody programs — including a randomized, double-blind, placebo-controlled trial of the long-acting anti-spike monoclonal sipavibart in long COVID patients at Nova Southeastern University — are directly evaluating whether anti-spike antibodies reduce both spike burden and symptoms. Third, mechanism-driven adjuncts targeting microclotting, endothelial dysfunction, inflammation, and autophagy are under early investigation (Davis et al., 2023; Hulscher et al., 2023).

Emerging immunologic work also raises an important caveat. Profiling of more than 140 individuals with long COVID identified persistent activation of chronic inflammatory networks distinct from fully recovered controls, suggesting that even if residual spike is present, clearing antigen alone may not reverse entrenched inflammatory signaling (Klein et al., 2023). A combined antiviral plus immunomodulatory approach may prove more effective than “detoxification” alone.

5. Safety Considerations

The McCullough protocol is sometimes presented as a benign over-the-counter regimen, but each component carries real clinical risk that must be assessed at the individual level.

5.1 Nattokinase

Nattokinase has fibrinolytic activity and is contraindicated, or requires close supervision, in patients on warfarin, direct oral anticoagulants, heparin, antiplatelet agents, or those with active bleeding disorders, recent surgery, or planned invasive procedures (Chen et al., 2018; Li et al., 2023). Case reports document serious bleeding complications, including a fatal intracerebral hemorrhage in an elderly patient and thrombotic complications when nattokinase was self-substituted for prescribed anticoagulation (Chen et al., 2018).

5.2 Bromelain

Bromelain carries similar antiplatelet effects and can potentiate bleeding when combined with nattokinase, NSAIDs, or anticoagulants. It is also a recognized allergen in patients with pineapple or latex sensitivity.

5.3 Curcumin

Curcumin is generally well tolerated but can interact with anticoagulants, antiplatelets, and CYP-metabolized drugs, and rare cases of hepatotoxicity have been reported with high-dose or formulated products. Patients with gallbladder disease or biliary obstruction should avoid high doses.

5.4 Peri-procedural risk

Because all three agents may increase bleeding risk, the protocol should generally be paused before any planned surgery or invasive procedure, with timing individualized in consultation with the surgical team. This is particularly relevant for patients undergoing colonoscopy, polypectomy, or any procedure with mucosal disruption.

6. Clinical Bottom Line

The McCullough protocol reflects one of several attempts to operationalize a persistent viral antigen model of long COVID using widely available oral agents. Its biological rationale is plausible, its individual components have decades of preclinical and limited cardiovascular human data, and a subset of patients with PASC do have measurable circulating spike antigen that, in theory, could be a target (Hulscher et al., 2023; Swank et al., 2023). However, current evidence is insufficient to recommend the regimen as a proven therapy for long COVID. There is no published randomized controlled trial demonstrating that it improves validated outcomes, and meaningful bleeding and drug-interaction risks accompany its use.

A defensible integrative position is the following: the protocol is best framed to patients as an experimental, mechanism-driven option, prescribed only after an individualized risk assessment, with informed consent that acknowledges the absence of randomized trial validation, with explicit attention to anticoagulant and antiplatelet co-therapies, and with structured re-evaluation at 3 and 6 months using validated symptom measures rather than indefinite continuation.

7. Conclusion

The McCullough base spike detoxification protocol is a biologically plausible but clinically unproven proposal. The 2023 Cureus paper that introduced it is an expert synthesis and clinical rationale, not a trial (Hulscher et al., 2023). Clinicians considering it should communicate the evidence level honestly, screen carefully for bleeding risk, document informed consent, and remain attentive to the emerging trial literature in anti-spike monoclonals, antiviral persistence trials, and immunomodulatory approaches. Long COVID care is moving quickly, and the standard of care five years from now will not be the standard of care today.

References

Chen, H., McGowan, E. M., Ren, N., Lal, S., Nassif, N., Shad-Kaneez, F., Qu, X., & Lin, Y. (2018). Nattokinase: A promising alternative in prevention and treatment of cardiovascular diseases. Biomarker Insights, 13, 1177271918785130. https://doi.org/10.1177/1177271918785130

Davis, H. E., McCorkell, L., Vogel, J. M., & Topol, E. J. (2023). Long COVID: Major findings, mechanisms and recommendations. Nature Reviews Microbiology, 21(3), 133–146. https://doi.org/10.1038/s41579-022-00846-2

Hulscher, N., Procter, B. C., Wynn, C., & McCullough, P. A. (2023). Clinical approach to post-acute sequelae after COVID-19 infection and vaccination. Cureus, 15(11), e49204. https://doi.org/10.7759/cureus.49204

Jaramillo, C. (2023, September 21). Posts push unproven ‘spike protein detoxification’ regimen. FactCheck.org. https://www.factcheck.org/2023/09/scicheck-posts-push-unproven-spike-protein-detoxification-regimen/

Klein, J., Wood, J., Jaycox, J. R., Dhodapkar, R. M., Lu, P., Gehlhausen, J. R., Tabachnikova, A., Greene, K., Tabacof, L., Malik, A. A., Silva Monteiro, V., Silva, J., Kamath, K., Zhang, M., Dhal, A., Ott, I. M., Valle, G., Peña-Hernández, M., Mao, T., … Iwasaki, A. (2023). Distinguishing features of long COVID identified through immune profiling. Nature, 623(7985), 139–148. https://doi.org/10.1038/s41586-023-06651-y

Li, X., Wang, F., Liu, M., Wang, P., Su, J., & Yu, X. (2023). Nattokinase supplementation and cardiovascular risk factors: A systematic review and meta-analysis of randomized controlled trials. Reviews in Cardiovascular Medicine, 24(8), 234. https://doi.org/10.31083/j.rcm2408234

Swank, Z., Senussi, Y., Manickas-Hill, Z., Yu, X. G., Li, J. Z., Alter, G., & Walt, D. R. (2023). Persistent circulating severe acute respiratory syndrome coronavirus 2 spike is associated with post-acute coronavirus disease 2019 sequelae. Clinical Infectious Diseases, 76(3), e487–e490. https://doi.org/10.1093/cid/ciac722

About Dr. Kim

Dr. Yoon Hang “John” Kim is a board-certified preventive medicine physician with more than 20 years of clinical experience in integrative and functional medicine. He completed an Osher Fellowship in Integrative Medicine at the University of Arizona under Dr. Andrew Weil, holds an Institute for Functional Medicine scholarship, and is certified in medical acupuncture through UCLA. His additional certifications span preventive medicine, integrative medicine, and holistic medicine.

Dr. Kim specializes in low-dose naltrexone (LDN) therapy, autoimmune conditions, chronic pain, integrative oncology, fibromyalgia, chronic fatigue syndrome, mast cell activation syndrome (MCAS), and mold-related illness. He is the author of three books and more than 20 peer-reviewed and clinical articles.

Professional site: www.yoonhangkim.com  |  Clinical practice: Direct Integrative Care