Harpagophytum procumbens
Harpagophytum
Grapple Plant
Wood Spider
Harpago
Garra del Diablo

---
canonical_name: Devil's Claw
alternate_names: Harpagophytum procumbens, Harpagophytum, Grapple Plant, Wood Spider, Harpago, Garra del Diablo
canonical_topic: Devil's Claw for Health & Longevity
short_topic_lc: devils_claw
creation_date: 2026-0617-0006
creator_ai_fullname: Opus 4.8
ep_keywords:
---

# Devil's Claw for Health & Longevity

Evidence Review created on 06/17/2026 using [AI4L](https://github.com/forever-healthy/AI4L) / Opus 4.8

**Also known as:** Harpagophytum procumbens, Harpagophytum, Grapple Plant, Wood Spider, Harpago, Garra del Diablo

## Motivation

Devil's Claw (*Harpagophytum procumbens*) is a flowering plant from the dry savannahs of southern Africa, named for the small hooked barbs on its fruit. The part used is the dried secondary root, taken as a capsule, tablet, tincture, or tea. Long valued in traditional medicine for joint aches and digestive complaints, it has become a widely sold over-the-counter remedy for pain and stiffness, with its main plant compound, harpagoside, often used as a marker of strength.

The plant draws interest because chronic joint pain and the daily wear of osteoarthritis are common companions of aging, and because long-term use of standard anti-inflammatory drugs carries real stomach, kidney, and heart costs. A gentler plant-based option that eases pain with fewer of those burdens is an appealing idea, and several clinical trials in back pain and arthritis have kept that idea alive.

This review examines what the evidence shows about Devil's Claw for easing joint and back pain, its possible wider effects, how it works, how it is dosed, where it may cause harm, and how strong or shaky the underlying science actually is.

**[Benefits](#expected-benefits) - [Risks](#potential-risks--side-effects) - [Protocol](#therapeutic-protocol) - [Conclusion](#conclusion)**

## Recommended Reading

This section lists high-quality overview content that introduces Devil's Claw and its therapeutic profile for readers who want broader context.

* [Devil's Claw (Harpagophytum procumbens) as a treatment for osteoarthritis: a review of efficacy and safety](https://pubmed.ncbi.nlm.nih.gov/17212570/) - Brien et al., 2006

  A focused narrative review of the osteoarthritis trial literature that frames the two practical questions a reader cares about — does it work and is it safe — and explains why methodological weaknesses leave both only partly answered.

* [Devil's Claw — a review of the ethnobotany, phytochemistry and biological activity of Harpagophytum procumbens](https://pubmed.ncbi.nlm.nih.gov/22940241/) - Mncwangi et al., 2012

  A wide-ranging review covering the plant's traditional uses, its active compounds, sustainability concerns from over-harvesting, and the recurring finding that the whole-root extract often outperforms its isolated marker compound.

* [The Fight against Infection and Pain: Devil's Claw (Harpagophytum procumbens) a Rich Source of Anti-Inflammatory Activity: 2011–2022](https://pubmed.ncbi.nlm.nih.gov/35684573/) - Gxaba & Manganyi, 2022

  A recent review that maps the anti-inflammatory and pain-relieving research of the last decade and candidly flags the gap between abundant laboratory data and the small number of modern human trials.

Only three items are listed because no relevant content from the priority experts could be found, and the remaining eligible non-systematic sources were too marginal to include without padding the list.

## Grokipedia

[Harpagophytum](https://grokipedia.com/page/Harpagophytum) - Grokipedia

The article covers the medicinal Devil's Claw genus, including its botany, native range in southern Africa, traditional uses, and the harpagoside-bearing root used in commercial pain and anti-inflammatory products.

## Examine

[Devil's Claw](https://examine.com/supplements/devlis-claw/) - Examine

Examine's monograph summarizes the human evidence for Devil's Claw in osteoarthritis and low back pain, its harpagoside-standardized dosing, and its safety profile, with study-by-study grading of the strength of each claim.

## ConsumerLab

No dedicated ConsumerLab article for Devil's Claw was found.

## Systematic Reviews

This section summarizes the systematic reviews and meta-analyses that evaluate Devil's Claw for musculoskeletal pain and safety, identified through a real-time PubMed search.

* [Harpagophytum procumbens for osteoarthritis and low back pain: a systematic review](https://pubmed.ncbi.nlm.nih.gov/15369596/) - Gagnier et al., 2004

  This review of twelve trials graded the evidence by extract type and harpagoside dose, finding strong evidence for an aqueous extract delivering 50 mg harpagoside daily in acute flare-ups of chronic non-specific low back pain and moderate evidence in osteoarthritis.

* [Herbal Medicine for Low Back Pain: A Cochrane Review](https://pubmed.ncbi.nlm.nih.gov/26630428/) - Gagnier et al., 2016

  An updated Cochrane review of fourteen randomized trials concluding that Devil's Claw reduces low back pain more than placebo, though the supporting evidence was rated moderate quality at best and no significant adverse events were seen.

* [Evidence of effectiveness of herbal medicinal products in the treatment of arthritis. Part I: Osteoarthritis](https://pubmed.ncbi.nlm.nih.gov/19856319/) - Cameron et al., 2009

  A systematic review of 35 trials of herbal products for osteoarthritis that found several Devil's Claw studies reported favorable effects on pain, while noting that no single product's effectiveness was proven beyond doubt.

* [Oral herbal medicines marketed in Brazil for the treatment of osteoarthritis: A systematic review and meta-analysis](https://pubmed.ncbi.nlm.nih.gov/28872719/) - Del Grossi Moura et al., 2017

  This meta-analysis of oral herbal osteoarthritis treatments found no significant benefit for Devil's Claw over control in the pooled data and rated the overall quality of evidence as low.

* [Systematic review on the safety of Harpagophytum preparations for osteoarthritic and low back pain](https://pubmed.ncbi.nlm.nih.gov/18236448/) - Vlachojannis et al., 2008

  A safety-focused review of 28 clinical trials reporting that adverse events with Devil's Claw were no more common than with placebo in blinded studies, with minor, mostly digestive complaints in about 3% of users and a call for more long-term data.

## Mechanism of Action

Devil's Claw's effects are attributed mainly to a group of plant compounds called iridoid glycosides, the most studied being harpagoside, along with harpagide, procumbide, and phenylpropanoid glycosides such as verbascoside. These compounds are concentrated in the secondary storage roots that are harvested for medicine.

The primary proposed mechanism is suppression of inflammation. Laboratory work indicates that Devil's Claw extracts and harpagoside dampen the production of pro-inflammatory signaling molecules — including TNF-α (tumor necrosis factor-alpha, a master inflammatory messenger), interleukins, and prostaglandins — and reduce activity of COX-2 (cyclooxygenase-2, the enzyme that conventional anti-inflammatory drugs block to make prostaglandins that drive pain and swelling). Extracts have also been shown to interfere with NF-κB (nuclear factor kappa B, a control switch that turns on many inflammatory genes), and harpagoside has reduced the formation of bone-degrading cells in laboratory models, a finding of potential relevance to joint disease.

A second proposed mechanism is direct pain relief and antioxidant activity. Animal studies suggest effects on pain signaling that are partly independent of inflammation, and the extracts can neutralize reactive oxygen species (unstable molecules that damage tissue).

A key competing mechanistic view concerns which compound matters. Harpagoside is used as the standardization marker, but several lines of evidence — including findings that whole-root extracts outperform isolated harpagoside, and that hydrolyzed breakdown products are more active — argue that efficacy cannot be ascribed to harpagoside alone and likely reflects the combined action of many root constituents. This unresolved question complicates dose standardization.

Devil's Claw is a botanical extract rather than a single pharmacological compound, so it has no single defined half-life, selectivity, or tissue distribution; available pharmacokinetic data are limited and are addressed in the Therapeutic Protocol section.

## Historical Context & Evolution

Devil's Claw has a long history of traditional use among the San and Khoikhoi peoples and other communities of the Kalahari region of southern Africa. The dried secondary root was prepared as decoctions, infusions, and ointments and used as a general health tonic and for a wide range of ailments — most notably joint and rheumatic pain, fever, digestive complaints and loss of appetite, and topically for sores, ulcers, and boils.

The plant entered European herbal medicine in the early twentieth century, after a German colonist reportedly observed its local use, and by mid-century extracts were being studied and marketed in Germany and France for arthritic and rheumatic conditions. Its move toward health optimization followed the broader search for plant-based alternatives to non-steroidal anti-inflammatory drugs (NSAIDs, the common painkillers such as ibuprofen), whose long-term use carries stomach, kidney, and cardiovascular risks. Interest grew through a series of European clinical trials in the 1990s and 2000s testing standardized extracts for low back pain and osteoarthritis.

The evolution of scientific opinion has been cautious rather than conclusive. Early observational and open trials were encouraging; later placebo-controlled trials and systematic reviews found genuine but modest signals, repeatedly limited by small samples, varied extract preparations, and short durations. Rather than a single overturned finding, the trajectory has been a stable picture of promising but methodologically weak evidence, with newer reviews continuing to call for larger, longer, well-designed trials before firm conclusions can be drawn. Sustainability concerns from over-harvesting of wild populations have also become a defining part of the plant's modern story.

## Expected Benefits

A dedicated search of clinical trials, systematic reviews, and expert sources was performed to compile the benefit profile below before grading. Benefits are framed for risk-aware adults considering Devil's Claw as part of a proactive joint-health and longevity strategy.

### Medium 🟩 🟩

#### Reduction of Low Back Pain

Devil's Claw is most consistently supported for short-term relief of chronic non-specific low back pain. The proposed mechanism is suppression of inflammatory mediators and prostaglandins in and around spinal soft tissue. A Cochrane review of randomized trials concluded it reduces low back pain more than placebo, with the strongest signal for an aqueous extract delivering roughly 50–100 mg harpagoside daily; the evidence was rated moderate quality at best, and trials were generally short (a few weeks) and modest in size.

**Magnitude:** In supportive trials, a meaningful share of users (roughly 1 in 5 at higher doses) became pain-free over 4 weeks versus far fewer on placebo; effect sizes are otherwise comparable to modest NSAID relief in short-term use.

#### Relief of Osteoarthritis Pain and Stiffness ⚠ Conflicted

Devil's Claw is widely used for knee, hip, and spinal osteoarthritis, where the same anti-inflammatory and pain-signaling mechanisms are proposed. The evidence is genuinely conflicted: several trials and narrative reviews report favorable reductions in pain and improved function, and one comparator trial found a powdered extract non-inferior to a prescription anti-inflammatory drug, but a meta-analysis of oral herbal osteoarthritis treatments found no significant benefit over control in pooled data and rated the evidence as low quality. The discrepancy likely reflects differences in extract type, harpagoside dose, trial duration, and outcome measures.

**Magnitude:** Where benefit is seen, pain scores improve on the order of 20–35% over 8–12 weeks versus placebo; pooled analyses that include negative trials show no clear net effect.

### Low 🟩

#### General Anti-Inflammatory Support

Beyond named joint conditions, Devil's Claw is taken as a broad anti-inflammatory aimed at the low-grade chronic inflammation linked to aging. Laboratory and animal studies show suppression of TNF-α, interleukins, COX-2, and NF-κB activity, providing a plausible mechanism, but human data on systemic inflammatory markers or hard longevity outcomes are sparse and indirect. For the longevity-oriented reader, this remains a mechanistically reasonable but clinically unproven use.

**Magnitude:** Not quantified in available studies.

#### Reduction of Reliance on NSAIDs

A practically important potential benefit is allowing some users to lower their dose of conventional painkillers, whose long-term use carries stomach, kidney, and cardiovascular risks. Some trials permitted rescue analgesia and reported reduced use in the Devil's Claw groups, suggesting a possible opioid- or NSAID-sparing role. Evidence is indirect and derives from secondary trial outcomes rather than dedicated studies.

**Magnitude:** Not quantified in available studies.

### Speculative 🟨

#### Digestive and Appetite Support

Traditional use includes Devil's Claw as a bitter tonic to stimulate appetite and ease mild digestive complaints, an effect attributed to its bitter iridoid compounds prompting digestive secretions. This use predates and is largely separate from the modern pain literature, and no controlled human trials substantiate it; the basis is traditional and mechanistic only.

#### Metabolic and Other Effects

Laboratory and animal studies have reported anti-diabetic, antioxidant, antimicrobial, antimalarial, and anti-epileptic activities of Devil's Claw extracts. These findings are early, derive almost entirely from non-human models, and have not been tested in humans; they are noted here only as directions of potential interest, not established benefits.

## Benefit-Modifying Factors

* **Genetic variation in drug metabolism:** Because the active iridoid glycosides are processed and broken down in the gut and liver, individual differences in metabolizing enzymes could in principle alter how much active compound reaches tissue, though no specific pharmacogenetic markers have been validated for Devil's Claw.

* **Baseline inflammation and pain severity:** Those with more active inflammatory joint pain may notice more benefit than those with low baseline symptoms, since the proposed mechanism is suppression of an ongoing inflammatory process.

* **Sex-based differences:** Osteoarthritis is more common and often more severe in women, and trial populations skew female; however, no reliable sex-specific difference in Devil's Claw response has been established, and trials have not been powered to detect one.

* **Pre-existing conditions:** Benefit is most evident in non-specific low back pain and osteoarthritis; people whose pain stems from causes other than inflammatory or degenerative joint disease are less likely to respond.

* **Age-related considerations:** Older adults — the group most affected by osteoarthritis and most exposed to NSAID harms — are the most likely to seek benefit, but they also tend to take more interacting medications and have reduced kidney and liver reserve, which can shift the balance of benefit and risk.

* **Extract type and harpagoside dose:** Benefit tracks strongly with preparation. Aqueous extracts standardized to higher harpagoside content (50–100 mg/day) show the clearest effects, while low-dose ethanolic extracts perform less well.

## Potential Risks & Side Effects

A dedicated search of drug-reference sources, safety-focused systematic reviews, and pharmacovigilance reports was performed to compile the risk profile below. Risks are framed for proactive adults weighing Devil's Claw against conventional analgesics.

### Medium 🟥 🟥

#### Gastrointestinal Upset

The most common adverse effect is mild digestive disturbance — diarrhea, nausea, abdominal discomfort, and loose stools — plausibly related to the bitter compounds stimulating digestive secretions and to the herb's traditional use as a digestive stimulant. Across controlled trials, gastrointestinal complaints occurred in roughly 3% of users and were generally no more frequent than with placebo. They are usually mild and reversible on stopping.

**Magnitude:** Reported in approximately 3% of users in pooled trial data; typically mild and self-limiting.

### Low 🟥

#### Gastric Irritation and Ulcer/Bleeding Concern ⚠ Conflicted

Because Devil's Claw acts partly through prostaglandin and COX-related pathways, a theoretical concern is irritation of the stomach lining similar to, though far milder than, NSAIDs, and some drug-safety bulletins have flagged reports of ulcers or gastrointestinal bleeding. The evidence is conflicted: controlled trials show no excess of serious gastrointestinal events versus placebo, while case-level pharmacovigilance signals and its prostaglandin-related mechanism justify caution, particularly in those with ulcer history or on blood thinners.

**Magnitude:** Serious gastrointestinal events not increased over placebo in controlled trials; rare case reports exist.

#### Blood Pressure and Heart Rhythm Effects

Animal and limited human observations suggest Devil's Claw may influence heart rate, blood pressure, and cardiac conduction, raising a theoretical concern for people with cardiovascular disease or those taking heart-rhythm or blood-pressure medications. Human data are sparse, and clinically significant cardiovascular events have not been documented in the trial literature, but the signal supports caution in vulnerable users.

**Magnitude:** Not quantified in available studies.

#### Allergic and Skin Reactions

As with many botanical products, allergic reactions including rash, itching, and rare hypersensitivity have been reported. The mechanism is standard plant-allergen sensitization, and such reactions are uncommon but warrant discontinuation if they occur.

**Magnitude:** Not quantified in available studies.

### Speculative 🟨

#### Pregnancy-Related Risk

Devil's Claw is traditionally avoided in pregnancy because of reports that it may stimulate uterine contractions (an oxytocic effect). No controlled human data exist; the concern rests on traditional knowledge and isolated reports, so pregnant and breastfeeding individuals are generally advised to avoid it.

#### Blood Sugar and Gallbladder Effects

Based on animal studies suggesting blood-sugar-lowering activity and on its bitter stimulant action on bile flow, theoretical concerns include additive glucose lowering in people on diabetes medication and aggravation of gallstones or bile-duct obstruction. These remain unconfirmed in humans and are mechanistic cautions only.

## Risk-Modifying Factors

* **Genetic variation in metabolism and clotting:** Variation in liver enzymes that process the active compounds, and in pathways affecting clotting, could theoretically influence both drug interactions and bleeding risk, though no validated Devil's Claw-specific genetic markers exist.

* **Baseline biomarkers:** Existing low blood pressure, low blood sugar, or abnormal liver or kidney function can amplify the herb's theoretical cardiovascular, metabolic, and clearance-related risks; baseline values help gauge susceptibility.

* **Sex-based differences:** No reliable sex-specific difference in adverse effects has been established; the pregnancy-related uterine-stimulation concern is, by definition, specific to people who can become pregnant.

* **Pre-existing conditions:** Risk is concentrated in people with active or prior peptic ulcer disease, gallstones, cardiovascular disease, diabetes, and bleeding disorders, in whom the gastrointestinal, cardiac, metabolic, and clotting concerns are most relevant.

* **Age-related considerations:** Older adults often have reduced kidney and liver reserve, take more interacting medications (including blood thinners and blood-pressure drugs), and bruise or bleed more easily, raising the practical importance of the bleeding and cardiovascular cautions.

## Key Interactions & Contraindications

* **Anticoagulants and antiplatelets:** Combining Devil's Claw with blood thinners (warfarin, and antiplatelet drugs such as clopidogrel, ticlopidine, and aspirin) may increase bleeding risk. Severity: caution to avoid; consequence: increased bleeding. Mitigation: avoid combination or monitor clotting closely under medical supervision.

* **NSAIDs and other gastric irritants:** Concurrent use with non-steroidal anti-inflammatory drugs (ibuprofen, naproxen) may add to gastric irritation. Severity: caution; consequence: stomach upset or ulcer risk. Mitigation: monitor for digestive symptoms; separate or limit combined use.

* **Antiarrhythmics and cardiac glycosides:** Because of possible effects on heart rate and conduction, caution is advised with heart-rhythm drugs and digoxin. Severity: caution; consequence: altered heart rhythm. Mitigation: avoid in those with arrhythmia or on these drugs without specialist oversight.

* **Antihypertensives:** Potential additive blood-pressure lowering with blood-pressure medications. Severity: caution; consequence: low blood pressure or dizziness. Mitigation: monitor blood pressure when starting.

* **Antidiabetic agents:** Theoretical additive blood-sugar lowering with diabetes medications (metformin, sulfonylureas, insulin). Severity: caution; consequence: low blood sugar. Mitigation: monitor glucose, especially early in use.

* **Drugs metabolized by liver enzymes:** Devil's Claw has shown laboratory effects on drug-metabolizing enzymes (including CYP-family enzymes that the liver uses to clear many medications, such as CYP3A4 and CYP2C9), so it could theoretically alter levels of co-administered drugs. Severity: caution; consequence: changed drug levels. Mitigation: review medication list with a clinician.

* **Acid-reducing drugs (over-the-counter):** Antacids and acid suppressants (such as omeprazole or famotidine) may blunt the herb's bitter, secretion-stimulating action and could affect dissolution; this is a minor, mechanistic interaction. Severity: monitor; consequence: possibly reduced effect. Mitigation: separate timing if relevant.

* **Supplements with additive effects:** Supplements that also thin the blood (fish oil, vitamin E, ginkgo, garlic), lower blood pressure (CoQ10, magnesium, hawthorn), lower blood sugar (berberine, cinnamon, alpha-lipoic acid), or relieve joint pain through anti-inflammatory action (turmeric/curcumin, Boswellia serrata, willow bark, ginger) may have additive effects with Devil's Claw — additive bleeding, blood-pressure, glucose, or anti-inflammatory effects respectively. Severity: caution; consequence: amplified effect. Mitigation: account for combined load and monitor.

* **Populations who should avoid Devil's Claw:** Pregnant individuals (possible uterine stimulation) and breastfeeding individuals (no safety data); people with active or prior peptic ulcer disease or gastrointestinal bleeding; those with gallstones or bile-duct obstruction; people with active arrhythmia or significant heart disease; and anyone on warfarin or other anticoagulants without medical supervision. Caution also applies to those with diabetes on glucose-lowering drugs and to people scheduled for surgery (stop at least 1–2 weeks beforehand owing to bleeding concerns).

## Risk Mitigation Strategies

* **Start low and assess tolerance:** Begin at the lower end of the dosing range for 1–2 weeks before increasing, which limits the most common risk — gastrointestinal upset — and lets unusual reactions surface early.

* **Take with food:** Dosing with meals reduces the gastric irritation and digestive-discomfort risk that arises from the herb's bitter, secretion-stimulating compounds and its prostaglandin-related action.

* **Screen for ulcer and bleeding risk:** People with prior peptic ulcer disease, gastrointestinal bleeding, or those on blood thinners should avoid Devil's Claw or use it only under medical supervision, directly addressing the ulcer/bleeding concern.

* **Stop before surgery:** Discontinue at least 1–2 weeks before any planned surgery or invasive dental work to mitigate the theoretical increased bleeding risk.

* **Monitor relevant biomarkers:** Those on antihypertensive, antidiabetic, or anticoagulant medication should monitor blood pressure, blood glucose, or clotting respectively when starting, to catch additive effects from interactions before they cause harm.

* **Choose standardized, third-party-tested products:** Selecting an extract standardized to a stated harpagoside content from a verified, contaminant-tested source mitigates the risk of under-dosing, adulteration with the related species *Harpagophytum zeyheri*, and contamination — protecting both efficacy and safety.

* **Avoid in pregnancy and breastfeeding:** Pregnant and breastfeeding individuals should not use Devil's Claw, mitigating the possible uterine-stimulation risk for which no safety data exist.

## Therapeutic Protocol

* **Standard dosing (low back pain):** Leading European clinical practice and the supportive trial evidence center on aqueous or hydroalcoholic root extracts standardized to harpagoside, typically delivering 50–100 mg of harpagoside per day. This corresponds to commonly studied extract doses in the range of roughly 600–2,400 mg of extract daily depending on the preparation's standardization.

* **Standard dosing (osteoarthritis):** Trials in osteoarthritis have used powdered root or aqueous extracts providing roughly 50–60 mg harpagoside daily; one comparator trial used an extract delivering about 60 mg harpagoside daily and compared it to a prescription anti-inflammatory drug.

* **Standardization to harpagoside:** Because preparations vary widely, practitioners emphasize choosing a product that states its harpagoside content; this is the practical handle for dosing, even though efficacy is not attributable to harpagoside alone.

* **Competing therapeutic approaches:** A conventional approach treats Devil's Claw as a standalone NSAID-sparing analgesic taken at a standardized harpagoside dose. An integrative approach instead positions it as one component of a multi-modal joint program alongside physical activity, weight management, and other anti-inflammatory agents (such as turmeric/curcumin or Boswellia serrata). Neither is presented here as the default; the choice depends on the user's goals and overall regimen.

* **Origin of the approaches:** The standardized-extract model was popularized largely through German and French phytotherapy and the European clinical trials of the 1990s–2000s that tested defined aqueous extracts; the integrative model reflects the broader functional and integrative medicine practice of combining botanicals with lifestyle measures.

* **Best time of day:** No strong evidence favors a particular time; taking it with meals is generally advised to reduce digestive upset, and splitting the dose across the day is common.

* **Expected half-life:** Pharmacokinetic data are limited. Harpagoside appears to be absorbed and cleared relatively quickly, with available estimates suggesting a short half-life on the order of several hours, which supports divided dosing.

* **Single vs. split dosing:** Because of the apparently short duration of action of the active compounds, daily intake is typically divided into two or three doses with meals rather than taken as a single dose.

* **Genetic considerations:** No validated pharmacogenetic markers guide Devil's Claw dosing; variation in liver enzymes that process the iridoid glycosides could in theory affect response but is not currently actionable.

* **Sex-based differences:** No established sex-specific dosing differences exist; trial populations have been predominantly female owing to the epidemiology of osteoarthritis.

* **Age-related considerations:** Older adults, the primary users, should favor lower starting doses given reduced organ reserve and the higher likelihood of interacting medications; dose can be titrated upward as tolerated.

* **Baseline biomarkers:** Those with abnormal kidney, liver, blood-pressure, or glucose values should have these considered before starting, as they bear on both interaction risk and clearance.

* **Pre-existing conditions:** People with osteoarthritis or non-specific low back pain are the populations in whom protocols have been tested; the protocol is not established for other pain sources.

## Discontinuation & Cycling

* **Short-term vs. lifelong use:** Devil's Claw is generally used as a symptomatic treatment for as long as pain relief is needed rather than as a lifelong daily supplement; most trial evidence covers only weeks to a few months, so long-term continuous use is not well studied.

* **Withdrawal effects:** No withdrawal syndrome has been described. Because the effect is symptomatic, the main consequence of stopping is the gradual return of the underlying joint or back pain it was masking.

* **Tapering:** No tapering protocol is required; the herb can be stopped abruptly without known rebound effects, though some users prefer to step down to confirm whether continued use is still providing benefit.

* **Cycling:** There is no established efficacy reason to cycle Devil's Claw. Some users take it intermittently — using it during symptom flares and pausing when pain subsides — which is a reasonable practical pattern given the symptomatic nature of its effect and the lack of long-term safety data.

* **Practical discontinuation triggers:** It should be stopped if gastrointestinal or allergic side effects appear, ahead of planned surgery, or if no meaningful benefit is noticed after an adequate trial of several weeks at a standardized dose.

## Sourcing and Quality

* **Species and adulteration:** *Harpagophytum procumbens* is the preferred medicinal species and contains higher levels of active compounds than its close relative *Harpagophytum zeyheri*, with which it is sometimes intentionally or accidentally mixed; look for products that specify *H. procumbens*.

* **Harpagoside standardization:** Choose extracts that state a defined harpagoside content (commonly standardized to 1–3% harpagoside, or to a stated milligram amount per dose), since this is the practical basis for matching the doses used in clinical trials.

* **Third-party testing:** Prefer products independently verified for potency, identity, and contaminants (heavy metals, microbes, adulterants) by programs such as USP, NSF, or independent laboratories, as botanical supplements are not tightly regulated and quality varies.

* **Reputable formats and brands:** Standardized aqueous or hydroalcoholic extracts from established European phytotherapy manufacturers most closely match the trial-tested preparations; whole-root powders are also available but vary more in active content.

* **Sustainability:** Wild Devil's Claw has been over-harvested, raising conservation concerns; sourcing from suppliers with certified sustainable or organic wild-harvesting practices supports both supply integrity and ethical sourcing.

## Practical Considerations

* **Time to effect:** Pain relief typically builds over weeks rather than acting immediately; trials generally assess outcomes at 4–12 weeks, and an adequate trial of at least several weeks at a standardized dose is needed before judging whether it works.

* **Common pitfalls:** The most frequent mistakes are using an under-dosed or non-standardized product that delivers too little harpagoside, expecting rapid relief and quitting too early, taking it on an empty stomach (increasing digestive upset), and overlooking interactions with blood thinners, blood-pressure, or diabetes medications.

* **Regulatory status:** In the United States, Devil's Claw is sold as a dietary supplement and is not FDA-approved as a drug, meaning products are not pre-market tested for efficacy or purity. In parts of Europe it is registered as a traditional herbal medicinal product for joint and back pain, which imposes stricter quality standards.

* **Cost and accessibility:** Devil's Claw is widely available over the counter and is generally inexpensive, so cost and access are not significant barriers for most users.

## Interaction with Foundational Habits

* **Sleep:** The interaction is indirect. Devil's Claw has no known direct effect on sleep architecture, but by easing joint and back pain it may improve sleep quality for those whose rest is disrupted by discomfort; there is no stimulant effect that would impair sleep, so timing relative to bedtime is not a concern.

* **Nutrition:** The interaction is direct in the sense that the herb is best taken with food to reduce digestive upset, and its bitter compounds may transiently stimulate digestive secretions and appetite. It pairs naturally with an overall anti-inflammatory dietary pattern (rich in vegetables, fatty fish, and olive oil), though no specific food must be avoided.

* **Exercise:** The interaction is potentiating and practical. By reducing musculoskeletal pain, Devil's Claw may make it easier to stay active, and physical activity and appropriate strengthening remain first-line for osteoarthritis and back pain; it does not blunt training adaptations, and there is no established need to time it around workouts beyond taking it with meals.

* **Stress management:** The interaction is indirect. There is no evidence Devil's Claw directly affects cortisol or the stress response, but chronic pain is itself a major physiological and psychological stressor, so any genuine pain relief may indirectly ease stress load; stress-reduction practices complement rather than interact with the herb.

## Monitoring Protocol & Defining Success

Before starting, a baseline assessment helps identify who is most likely to benefit and who carries elevated risk, particularly people on interacting medications or with relevant pre-existing conditions. Baseline testing should include a record of current pain and function, plus the laboratory markers below where the user has cardiovascular, metabolic, bleeding, or organ-function concerns or takes interacting drugs.

Ongoing monitoring is primarily symptom-based, with laboratory checks reserved for those on relevant co-medications. A reasonable cadence is a symptom and tolerability review at 4 weeks and again at 8–12 weeks to judge whether an adequate trial has produced benefit, then periodically (every 6–12 months) for continued users, with biomarker checks at baseline and as clinically indicated when interacting medications are involved.

| Biomarker | Optimal Functional Range | Why Measure It? | Context/Notes |
|-----------|--------------------------|-----------------|---------------|
| Pain score (e.g., VAS, 0–10) | Reduction of ≥2 points or ≥30% from baseline | Tracks the primary intended benefit | VAS = Visual Analogue Scale, a self-rated pain ruler; reassess at 4 and 8–12 weeks |
| Function score (e.g., WOMAC) | Meaningful improvement from baseline | Captures stiffness and daily-activity impact, not just pain | WOMAC = a standard osteoarthritis questionnaire; most relevant for knee/hip OA |
| INR (if on warfarin) | Within the individual's target range (often 2.0–3.0) | Detects added bleeding risk from herb–drug interaction | INR = International Normalized Ratio, a clotting-time measure; check more often when starting or stopping |
| Fasting glucose | 70–90 mg/dL | Flags additive blood-sugar lowering in people on diabetes drugs | Requires fasting; most relevant if on glucose-lowering medication |
| Blood pressure | <120/80 mmHg | Detects additive blood-pressure lowering | Measure seated after rest; relevant if on antihypertensives |
| ALT / AST | <25 U/L (men), <20 U/L (women), functional target | Screens liver function given hepatic metabolism and rare hepatic concerns | ALT/AST = liver enzymes; conventional upper limits run higher (~40 U/L) |
| eGFR | >90 mL/min/1.73m² | Gauges kidney reserve, relevant for older users on multiple drugs | eGFR = estimated kidney filtration rate; pairs with a basic metabolic panel |

Qualitative markers complement the lab and score data and are often the most meaningful sign of success for the user.

* Morning joint stiffness and how long it lasts on waking
* Ease and range of everyday movement (climbing stairs, rising from a chair)
* Reliance on other painkillers, including whether NSAID or other analgesic use has fallen
* Sleep quality, particularly whether pain-related awakenings have decreased
* Overall energy and ability to stay physically active

## Emerging Research

* **Standardized extract in knee osteoarthritis (recent trial):** A multicenter, randomized, double-blind trial ([NCT05925725](https://clinicaltrials.gov/study/NCT05925725)) evaluated a Devil's Claw-containing dietary supplement (Loxacon) in 100 patients with knee osteoarthritis (Phase 4, completed 2023), using the WOMAC osteoarthritis index and pain (VAS) as primary endpoints. Results of this kind of well-controlled, modern trial are exactly what reviews have called for to firm up the osteoarthritis evidence.

* **Dose-finding and safety trial (illustrating the evidence gap):** An earlier UK dose-ranging trial ([NCT00295490](https://clinicaltrials.gov/study/NCT00295490)) aimed to compare three doses of Devil's Claw against placebo for hip and knee osteoarthritis over 16 weeks but was terminated, with 67 participants — a concrete example of how recruitment and conduct difficulties have limited the field and left key dosing questions open.

* **Identifying the true active compounds:** A recurring future-research direction, highlighted by Mncwangi et al. ([2012](https://pubmed.ncbi.nlm.nih.gov/22940241/)), is moving beyond harpagoside as the sole marker to characterize the full mixture of root constituents responsible for activity, since whole extracts outperform isolated harpagoside; this could change how products are standardized and dosed.

* **Closing the lab-to-human gap:** Gxaba & Manganyi ([2022](https://pubmed.ncbi.nlm.nih.gov/35684573/)) note that abundant in vitro anti-inflammatory findings have not been matched by modern in vivo clinical studies, and that filling this gap is the key to validating — or tempering — the broader anti-inflammatory and metabolic claims that could strengthen or weaken the case for the plant.

* **Sustainability and standardization research:** Work on cultivation, sustainable harvesting, and rapid quality-control methods to distinguish *H. procumbens* from *H. zeyheri* could improve product consistency, which in turn would make future efficacy trials more interpretable.

## Conclusion

Devil's Claw is a root extract from a southern African plant, used for centuries for pain and taken today mainly to ease the joint and back pain of conditions like osteoarthritis. Its appeal for health- and longevity-minded users lies in offering plant-based pain relief that may lean less on standard painkillers, whose long-term stomach, kidney, and heart costs are well known. The most consistent evidence supports short-term relief of ongoing low back pain, with a real but conflicting signal for osteoarthritis pain and stiffness; broader anti-inflammatory and metabolic uses remain unproven in people.

The main drawbacks are usually mild and digestive, though caution is warranted for those on blood thinners, blood-pressure or blood-sugar medicines, those with ulcers, and during pregnancy. Crucially, the science is promising but shaky: most trials have been small, short, and built on differing preparations, leaving the overall picture suggestive rather than firm. Product quality varies widely, making a standardized, independently tested extract important. Overall, Devil's Claw emerges as a generally well-tolerated option with modest, mainly short-term evidence for pain relief, sitting on an evidence base that is suggestive rather than settled.

**[Top](#top) - [Benefits](#expected-benefits) - [Risks](#potential-risks--side-effects) - [Protocol](#therapeutic-protocol)**


Double Filtration Plasmapheresis
Therapeutic Plasma Exchange
Plasmapheresis
Plasma Exchange
PLEX
Cascade Filtration

---
canonical_name: DFPP vs. TPE
alternate_names: Double Filtration Plasmapheresis, Therapeutic Plasma Exchange, Plasmapheresis, Plasma Exchange, PLEX, Cascade Filtration
canonical_topic: DFPP vs. TPE for Health & Longevity
short_topic_lc: dfpp_vs_tpe
creation_date: 2026-0711-0352
creator_ai_fullname: Opus 4.8
---

# DFPP vs. TPE for Health & Longevity

Evidence Review created on 07/11/2026 using [AI4L](https://github.com/forever-healthy/AI4L) / Opus 4.8

**Also known as:** Double Filtration Plasmapheresis, Therapeutic Plasma Exchange, Plasmapheresis, Plasma Exchange, PLEX, Cascade Filtration

## Motivation

The blood carries oxygen and nutrients but also a shifting mix of proteins, antibodies, fats, and waste that accumulates inflammatory and damage-signaling molecules with age. Two established procedures aim to clean it directly. Therapeutic plasma exchange removes much of the liquid part of the blood and replaces it with a substitute solution. Double filtration plasmapheresis instead passes the blood through two filters, trapping the largest, most harmful molecules while returning most of the useful ones. Both have long treated immune and cholesterol disorders and are now studied as ways to influence aging itself.

The idea that refreshing the blood might rejuvenate the body grew from decades of animal experiments in which older animals appeared biologically younger after sharing circulation with young ones. Later work suggested the benefit came less from adding youthful ingredients than from diluting aged ones, turning attention toward filtering methods that healthy older adults could, in principle, undergo repeatedly.

This review examines these two blood-filtering approaches considered for general health and longevity rather than a single disease. It compares how each works, what benefits and risks the evidence supports, and how they differ in selectivity, cost, and safety, while noting where the science remains uncertain.

**[Benefits](#expected-benefits) - [Risks](#potential-risks--side-effects) - [Protocol](#therapeutic-protocol) - [Conclusion](#conclusion)**

## Recommended Reading

This section presents high-level, expert-facing resources on therapeutic plasma exchange (TPE) and double filtration plasmapheresis (DFPP) viewed through a longevity lens.

* [Q&A #14 with Dr. Rhonda Patrick (8/1/2020)](https://www.foundmyfitness.com/episodes/qa-14-dr-rhonda-patrick) - Rhonda Patrick

  Patrick walks through the plasma-dilution mouse work that reframed the "young blood" story as removal of pro-aging factors, giving a scientist's read on why blood filtration, not youthful infusion, may be the active ingredient.

* [Young Blood & Longevity: Therapeutic Plasma Exchange (TPE) Treatments](https://www.diamandis.com/blog/young-blood-and-longevity-tpe) - Peter Diamandis

  A physician-entrepreneur's accessible overview of how plasma exchange is being marketed and studied for age reversal, useful for understanding both the enthusiasm and the commercial framing surrounding the field.

* [Dr. Dobri Kiprov, M.D. – Pioneer in Therapeutic Plasma Exchange](https://dobrikiprov.com/) - Dobri Kiprov

  The site of the apheresis physician who led the first randomized longevity plasma-exchange trial, laying out the clinical rationale for repeated exchange in older adults from the perspective of its leading proponent.

* [Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin](https://pubmed.ncbi.nlm.nih.gov/32474458/) - Mehdipour et al., 2020

  The foundational primary study showing that simply diluting aged plasma with a saline-albumin solution rejuvenated brain, liver, and muscle in old mice, the biological basis most often cited for exchange-based longevity protocols.

* [A randomized, controlled clinical trial of plasma exchange with albumin replacement for Alzheimer's disease: Primary results of the AMBAR Study](https://pubmed.ncbi.nlm.nih.gov/32715623/) - Boada et al., 2020

  The largest controlled human trial of repeated plasma exchange for an age-related brain disease, offering the clearest picture to date of what sustained exchange can and cannot achieve clinically.

Dedicated, substantive content specifically on plasma exchange or plasmapheresis could not be confirmed from Peter Attia, Andrew Huberman, or Chris Kresser at the time of writing; where these experts touch the topic it is brief and within broader discussions of parabiosis. Life Extension has covered plasma and age-reversal research, but its articles were not reliably accessible for citation.

## Grokipedia

* [Plasmapheresis](https://grokipedia.com/page/Plasmapheresis)

  Grokipedia's primary article covers plasmapheresis as an umbrella procedure, describing both replacement-based therapeutic plasma exchange and filtration methods, their indications, and their mechanics, which frames the comparison at the center of this review.

## Examine

No Examine article exists for double filtration plasmapheresis or therapeutic plasma exchange. Examine's scope is limited to dietary supplements, foods, and nutrients, and it does not publish pages on medical procedures such as apheresis.

## ConsumerLab

No ConsumerLab article exists for double filtration plasmapheresis or therapeutic plasma exchange. ConsumerLab tests and reviews supplements and packaged health products, so procedural interventions such as plasma exchange fall outside its coverage.

## Systematic Reviews

The following systematic reviews and meta-analyses summarize the controlled evidence for therapeutic plasma exchange and double filtration plasmapheresis across their established clinical uses, which anchor any longevity extrapolation.

* [Efficacy and safety of double-filtration plasmapheresis treatment of myasthenia gravis: A systematic review and meta-analysis](https://pubmed.ncbi.nlm.nih.gov/33907116/) - Liu et al., 2021

  Pooling nine controlled studies, this is the best DFPP-specific synthesis, reporting substantially higher remission (odds ratio [OR] 4.33, 95% confidence interval [CI] 1.97–9.53) and confirming that selective filtration lowers pathogenic antibodies.

* [The effects of plasma exchange in patients with ANCA-associated vasculitis: an updated systematic review and meta-analysis](https://pubmed.ncbi.nlm.nih.gov/35217545/) - Walsh et al., 2022

  In this antibody-driven blood-vessel inflammation (ANCA-associated vasculitis), the synthesis shows plasma exchange reduces kidney failure but raises serious infections (relative risk [RR] 1.27), a critical reminder that removing antibodies indiscriminately carries a real immune cost.

* [Plasma exchange for acute and acute-on-chronic liver failure: A systematic review and meta-analysis](https://pubmed.ncbi.nlm.nih.gov/37530812/) - Beran et al., 2024

  Analyzing thousands of patients, it demonstrates a survival benefit of plasma exchange in liver failure, illustrating that removing accumulated protein-bound toxins can change hard outcomes.

* [Efficacy and safety of blood derivatives therapy in Alzheimer's disease: a systematic review and meta-analysis](https://pubmed.ncbi.nlm.nih.gov/36443888/) - Fei et al., 2022

  This review evaluates plasma exchange and related blood-derivative approaches in Alzheimer's disease, the age-related condition where exchange has been most rigorously tested, and weighs the modest and mixed signal.

* [The Safety and Efficacy of Regional Citrate Anticoagulation in Therapeutic Plasma Exchange: A Systematic Review and Meta-Analysis](https://pubmed.ncbi.nlm.nih.gov/41420369/) - Liu et al., 2026

  Focused on procedural safety, it compares anticoagulation strategies during exchange, directly relevant to the citrate-related side effects that dominate the risk profile of elective, repeated apheresis.

## Mechanism of Action

Both procedures are extracorporeal blood-purification techniques: blood is drawn out, separated, cleaned, and returned. They are procedures, not pharmacological compounds, so drug properties such as half-life, tissue distribution, and enzyme-based metabolism do not apply; what matters instead is which molecules are removed and how completely.

In **therapeutic plasma exchange (TPE)**, a machine separates whole plasma from blood cells (by spinning it in a centrifuge or pushing it across a large-pore membrane) and discards roughly one to one-and-a-half plasma volumes, returning the cells together with a replacement fluid — usually 5% albumin (the main blood protein) or, less often, fresh frozen plasma (FFP, donor plasma used as a replacement fluid). Because the whole plasma is removed, TPE is **non-selective**: it strips out antibodies, immune complexes, inflammatory signaling proteins, and cholesterol particles alongside beneficial proteins, then replaces the deficit with donor material.

In **double filtration plasmapheresis (DFPP)**, the first filter separates plasma from cells exactly as in TPE, but the plasma then passes through a second "plasma fractionator" whose pore size sets a molecular-weight cutoff. Large molecules — low-density lipoprotein (LDL, the main cholesterol-carrying particle linked to artery disease), lipoprotein(a) (Lp(a), an inherited, especially atherogenic cholesterol particle), immunoglobulin M (IgM) and much immunoglobulin G (IgG) (the two main antibody classes), fibrinogen (a clotting protein), and immune complexes — are retained and discarded, while smaller proteins including most albumin are returned. DFPP is therefore **size-selective** and largely **albumin-sparing**, needing little or no external replacement fluid.

For the longevity hypothesis, two competing mechanistic explanations coexist and both are presented here. The first, the **removal/dilution model**, holds that aging blood carries an excess of pro-aging factors — pro-inflammatory cytokines ("inflammaging"), the senescence-associated secretory phenotype (SASP, the mix of inflammatory molecules secreted by worn-out "senescent" cells), oxidized lipids, and autoantibodies — and that lowering their concentration quiets damaging signaling long enough to reset gene expression in multiple tissues. The second, the **proteostatic-reset model**, proposes that the sharp drop in plasma proteins triggers a compensatory wave of fresh hepatic protein synthesis, effectively renewing the plasma proteome. A skeptical counter-view notes that removed factors re-accumulate within days, so any benefit may be transient unless treatment is repeated, and that much of the human enthusiasm rests on surrogate biomarkers rather than outcomes.

## Historical Context & Evolution

Plasmapheresis was first described in 1914 in animal experiments, but therapeutic use expanded from the 1950s onward as machines made large-volume separation practical. TPE became a standard treatment for conditions driven by harmful plasma factors — thrombotic thrombocytopenic purpura (TTP), Guillain-Barré syndrome (GBS), myasthenia gravis (MG), and hyperviscosity syndromes — and the American Society for Apheresis (ASFA) now grades indications by strength of evidence. DFPP was developed in Japan in the late 1970s and 1980s as "cascade filtration," specifically to reduce the large volumes of donor replacement fluid that conventional exchange required; it became widely used in Japan and China for high cholesterol, autoimmune disease, and blood-flow (rheologic) disorders.

The original intended use of both procedures was thus disease-specific removal of a known pathogenic substance, not general health optimization. The pivot toward longevity came from a separate line of research: parabiosis experiments, in which two animals share a circulation. Mid-twentieth-century and then landmark 2005 heterochronic parabiosis studies showed that old tissue regained youthful regenerative capacity when exposed to young blood. Rather than being dismissed, these findings were reinterpreted — later blood-exchange and plasma-dilution work suggested the effect was driven substantially by diluting old, pro-aging factors rather than by any youth-restoring ingredient in young blood. This reinterpretation is what made a filtration or exchange procedure, performed on a single older individual without any young donor, a plausible longevity tool.

The evolution of opinion here is genuinely unsettled and should not be framed as settled in either direction. Enthusiasts point to consistent animal rejuvenation and early positive human biomarker trials; skeptics point to failed or ambiguous "young plasma" infusion trials and a regulatory warning against unproven anti-aging blood products. What changed most recently is the arrival of controlled human trials measuring biological-age markers, which have shifted the debate from pure theory toward testable, if still preliminary, human data.

## Expected Benefits

Benefits are graded by strength of evidence and framed for a health- and longevity-oriented adult weighing elective, repeated use rather than for an acutely ill patient.

### High 🟩 🟩 🟩

#### Removal of Atherogenic Lipoproteins (LDL and Lp(a))

Both procedures physically strip cholesterol-carrying particles from the blood, but DFPP is especially efficient because its second filter is sized to trap large LDL and Lp(a) particles while returning smaller proteins. Decades of use in familial hypercholesterolemia (FH, an inherited condition causing very high cholesterol) — supported by registry data and a systematic review of lipoprotein apheresis — show large, reproducible reductions in these particles and, in the highest-risk patients, fewer cardiovascular events. Because Lp(a) is largely resistant to drugs and diet, physical removal is one of the few effective options, which is directly relevant to a longevity-focused adult with an elevated inherited risk.

**Magnitude:** A single session typically lowers LDL and Lp(a) by roughly 60–70%; with regular treatment, time-averaged reductions of about 30–50% are sustained.

#### Clearance of Pathogenic Antibodies and Immune Complexes

The best-established action of both procedures is bulk removal of circulating antibodies and immune complexes, the mechanism behind their approved use in autoimmune neurologic and kidney disease. Controlled evidence, including the DFPP meta-analysis in myasthenia gravis and plasma-exchange syntheses in vasculitis, confirms rapid, measurable lowering of autoantibodies with corresponding clinical improvement. For the longevity audience, this establishes that repeated exchange reliably reduces the antibody and immune-complex burden that also rises with age.

**Magnitude:** One exchange of 1–1.5 plasma volumes removes roughly 60–65% of circulating IgG in a session and a higher fraction of larger antibodies such as IgM.

### Medium 🟩 🟩

#### Reduction of Inflammatory and Senescence-Associated Factors (Inflammaging)

Aging is accompanied by a chronic, low-grade rise in inflammatory signaling proteins, and both procedures physically remove them from plasma. A comparative crossover study measured clearance of interleukin-6 (IL-6, a pro-inflammatory signaling protein) and tumor necrosis factor-alpha (TNF-α, another pro-inflammatory signaling protein) during exchange, and mechanistic work links dilution of these factors to quieter damage signaling. The main limitation is durability: levels partially rebound within days, so any anti-inflammatory effect is intermittent unless treatment is repeated.

**Magnitude:** Single sessions measurably lower IL-6 and TNF-α, though concentrations partially rebound within days.

#### Reduction in Biological-Age Markers (Epigenetic Clocks) ⚠ Conflicted

The most direct longevity evidence comes from a randomized, placebo-controlled trial in adults over 50 in which repeated TPE, especially when paired with intravenous immunoglobulin (IVIG, concentrated donor antibodies given by infusion), shifted multiple epigenetic clocks toward a younger profile and improved immune-aging markers. Evidence is flagged as conflicted because separate "young plasma" infusion trials in older adults were largely null, epigenetic-clock changes are surrogate markers of uncertain durability, and the strongest positive trial was small and run by parties with a commercial interest in the procedure. The signal is real but preliminary and not yet linked to any hard health outcome.

**Magnitude:** In the randomized trial, repeated exchange shifted several epigenetic clocks roughly 2–3.6 years younger versus placebo.

#### Improved Blood Rheology and Microcirculation

DFPP in particular lowers plasma fibrinogen and viscosity, improving blood flow through small vessels — the historical basis for its use in sudden hearing loss, peripheral artery disease, and diabetic microvascular complications. Because impaired microcirculation contributes to tissue aging, this is a plausible longevity-relevant benefit, supported by rheology studies though not by long-term outcome trials in healthy people. TPE lowers fibrinogen as well but less selectively.

**Magnitude:** DFPP lowers plasma fibrinogen by roughly 40–60% per session, measurably reducing blood viscosity.

### Low 🟩

#### Slowing of Cognitive Decline in Alzheimer's Disease

Repeated plasma exchange with albumin replacement was tested in a dedicated randomized program in mild-to-moderate Alzheimer's disease, with a signal of slowed functional and cognitive decline, particularly in moderate-stage patients. The evidence is graded Low for a general longevity audience because it applies to an established disease population, the effect was modest, and the program was funded by the manufacturer of the albumin used. It nonetheless demonstrates that sustained exchange can influence an age-related brain disease.

**Magnitude:** In moderate-stage patients, the randomized program slowed decline on a daily-function scale by roughly 60% over about a year.

#### Removal of Protein-Bound Environmental Contaminants

Interest is growing in using DFPP to lower the body burden of persistent contaminants such as per- and polyfluoroalkyl substances (PFAS, persistent industrial "forever chemicals") and, more speculatively, microplastic particles, because these bind plasma proteins that the second filter removes. Occupational studies of apheresis and plasma donation show meaningful per-session reductions in PFAS, and a dedicated DFPP microplastic-reduction trial is underway. Whether lowering these burdens improves health or longevity outcomes is unproven.

**Magnitude:** Apheresis lowers blood PFAS by a meaningful fraction per session in occupational studies, but the health benefit of doing so is not yet established.

### Speculative 🟨

#### Extension of Healthspan or Lifespan

Animal work — plasma dilution rejuvenating multiple tissues, and young-plasma treatment extending mean lifespan in rats — raises the possibility that periodic blood filtering could extend healthy lifespan in humans. No human lifespan or healthspan outcome data exist; the basis is mechanistic and cross-species only, and rebound of removed factors is a major unknown.

#### Enhanced Tissue Regenerative and Stem-Cell Capacity

Diluting aged plasma restored the function of muscle, liver, and brain stem-cell niches in mice, suggesting exchange might renew regenerative capacity in aging humans. This remains hypothetical: human tissue-regeneration endpoints have not been measured after exchange, and the durability of any niche effect is unknown.

## Benefit-Modifying Factors

* **Genetic polymorphisms:** Carriers of high-risk lipid variants — for example in the *LPA* gene driving Lp(a) or in *LDLR* (the gene for the receptor that clears LDL cholesterol) — start with a much higher removable burden and stand to gain most from DFPP lipid clearance. In Alzheimer's exchange data, *APOE4* (a common gene variant that raises Alzheimer's risk and affects fat metabolism) carriers appeared to respond differently, so genotype may shape brain benefit.
* **Baseline biomarker levels:** Benefit tends to scale with what is there to remove; individuals with high baseline Lp(a), LDL, inflammatory markers, or autoantibodies see larger absolute reductions than those already near optimal levels.
* **Sex-based differences:** Women have a smaller estimated plasma volume for a given body weight, so a "standard" exchange clears a slightly different fraction; hormone-related differences in lipid and inflammatory profiles may also alter which factors dominate the removable pool.
* **Pre-existing health conditions:** People with familial hypercholesterolemia, antibody-mediated autoimmune disease, or hyperviscosity have a defined pathogenic target and derive the clearest benefit; a metabolically healthy adult has a smaller and less certain target.
* **Age:** Older adults within the target range carry a heavier load of inflammatory and senescence-associated factors, so the theoretical upside is larger — but this is partly offset by reduced physiologic reserve and higher procedural risk.

## Potential Risks & Side Effects

Risks are graded by strength of evidence and framed for an elective, repeated-use context in a relatively healthy adult, where tolerance for procedural harm is lower than in acute disease.

### High 🟥 🟥 🟥

#### Hypocalcemia from Citrate Anticoagulation

Both procedures use citrate to keep blood from clotting in the circuit, and citrate binds calcium, transiently lowering ionized calcium. This produces tingling around the mouth and fingers, muscle cramps, and, rarely, more serious rhythm or muscle effects; it is the single most common side effect of apheresis. It is generally mild, predictable, and reversible with calcium supplementation and slower citrate delivery.

**Magnitude:** Symptomatic low-calcium events occur in roughly 1.5–9% of procedures and are usually mild and self-limited.

#### Hypotension and Fluid Shifts

Moving large volumes of blood and plasma through an external circuit causes shifts in blood volume that can drop blood pressure, producing lightheadedness, nausea, or fainting. The risk is higher with larger exchanges, poor cardiac reserve, or inadequate replacement fluid, and it is one of the most frequently reported adverse events across apheresis registries. It is usually managed by adjusting flow rates and replacement.

**Magnitude:** Transient low blood pressure and related vasovagal reactions occur in up to roughly 10% of sessions.

### Medium 🟥 🟥

#### Coagulopathy and Bleeding from Clotting-Factor Depletion

Because fibrinogen and other clotting factors are large proteins, they are removed along with the target molecules — DFPP lowers fibrinogen especially sharply. This transiently raises bleeding risk until the liver resynthesizes the factors over one to two days, and it compounds with any anticoagulant or antiplatelet medication the person takes. Spacing sessions and monitoring fibrinogen mitigate the risk.

**Magnitude:** Fibrinogen and clotting factors can fall 40–60% per session, transiently increasing bleeding risk until they re-synthesize over 1–2 days.

#### Allergic and Anaphylactoid Reactions to Replacement Fluid

Reactions range from hives and fever to, rarely, anaphylaxis, and are driven mainly by the replacement fluid: donor fresh frozen plasma carries the highest rate, while albumin is far safer. A distinct and dangerous anaphylactoid reaction can occur when negatively charged DFPP membranes or columns are used in someone taking certain blood-pressure drugs, through a bradykinin mechanism. Choosing albumin over donor plasma sharply reduces the everyday allergic risk.

**Magnitude:** Reactions are common with donor-plasma replacement (up to roughly 20%, mostly mild) but uncommon with albumin (well under a few percent).

#### Vascular Access Complications and Infection

Repeated procedures often require reliable venous access; when a central venous catheter is used, it brings risks of bloodstream infection, clot formation, and mechanical injury. These risks accumulate with the number of catheter-days, which is a particular concern for elective longevity protocols involving many sessions over time. Peripheral access, where feasible, avoids most of this.

**Magnitude:** Central-line bloodstream infection and thrombosis risk scales with catheter-days; peripheral access largely avoids it.

### Low 🟥

#### Immunoglobulin Depletion and Infection Susceptibility

Repeated exchange progressively lowers protective antibodies, and pooled trial data in autoimmune disease show a measurable rise in serious infections. For a healthy adult undergoing elective repeated exchange, cumulative antibody depletion is a plausible but under-studied harm, and it is one rationale for occasionally pairing exchange with immunoglobulin replacement. Monitoring IgG over a course helps detect meaningful depletion.

**Magnitude:** Pooled trial data in one autoimmune condition showed serious infections rose about 27% (relative risk 1.27) with repeated exchange.

#### Removal of Beneficial Factors and Therapeutic Drugs

Because TPE is non-selective, it also removes clotting factors, hormones, protective antibodies, and any highly protein-bound medications, which can drop drug levels unpredictably around a session. This can reduce the effect of a needed medication or, conversely, require re-dosing at the wrong time. DFPP's selectivity reduces but does not eliminate this concern.

**Magnitude:** Highly protein-bound drugs can fall unpredictably per session, so dosing must be timed around procedures.

### Speculative 🟨

#### Rebound Overproduction of Pathogenic Factors

Sharp removal of a plasma constituent can provoke a homeostatic rebound in which the body overshoots baseline production, theoretically worsening the very factor that was removed. This is documented for some antibodies after exchange but has not been quantified for inflammatory or senescence factors in a longevity context.

#### Unknown Long-Term Effects of Elective Repeated Apheresis in Healthy Adults

The entire evidence base for repeated exchange comes from people with disease; the long-term consequences of subjecting an otherwise healthy person to many exchanges over years — on immune competence, protein homeostasis, and vascular access — are simply unknown and rest on extrapolation only.

## Risk-Modifying Factors

* **Genetic polymorphisms:** Inherited clotting disorders or low baseline fibrinogen raise bleeding risk from factor depletion, while variants affecting complement or bradykinin handling may predispose to anaphylactoid reactions during filtration.
* **Baseline biomarker levels:** Low starting ionized calcium, low fibrinogen, low IgG, or low albumin all narrow the safety margin, since each falls further during the procedure; these should be checked before a series.
* **Sex-based differences:** Because women generally have a smaller plasma volume, a fixed exchange volume removes a larger proportion of their clotting factors and antibodies, modestly increasing depletion-related risk per session.
* **Pre-existing health conditions:** Heart failure and coronary disease raise the danger of fluid-shift hypotension; active infection is worsened by antibody removal; and use of blood-pressure medications in the ACE inhibitor class (angiotensin-converting enzyme inhibitors, a common blood-pressure drug class) sharply raises anaphylactoid-reaction risk with certain filters.
* **Age:** Older adults in the target range have less cardiovascular and immune reserve, so the same fluid shifts, calcium drops, and antibody losses are less well tolerated than in younger people.

## Key Interactions & Contraindications

* **ACE inhibitors (e.g., lisinopril, ramipril, enalapril):** Absolute contraindication with negatively charged DFPP and lipoprotein-apheresis membranes/columns — the combination triggers bradykinin-mediated anaphylactoid reactions with severe flushing and hypotension. Mitigation: withhold ACE inhibitors for at least 24–48 hours before treatment, or switch drug class in consultation with a physician.
* **Anticoagulants and antiplatelets (e.g., warfarin, apixaban, clopidogrel, aspirin):** Caution — additive bleeding risk on top of procedure-induced fibrinogen and clotting-factor depletion. Mitigation: monitor fibrinogen, keep it above 100 mg/dL, and time or hold agents around sessions.
* **Highly protein-bound medications (e.g., levothyroxine, warfarin, some antibiotics, valproate):** Caution — these are partly removed by exchange, causing unpredictable drops in level. Mitigation: dose after, not before, a session and monitor where a therapeutic level matters.
* **Recently administered biologic antibodies and IVIG:** Caution — monoclonal antibody drugs and infused immunoglobulin are removed by exchange, blunting their effect. Mitigation: separate timing, giving such agents after the exchange.
* **Supplement interactions (blood-thinning supplements: fish oil, high-dose vitamin E, *Ginkgo biloba*, garlic, nattokinase):** Caution — additive bleeding risk with clotting-factor depletion; consider pausing before a session.
* **Additive-effect supplements and drugs (statins, PCSK9 inhibitors — a class of injectable cholesterol-lowering drugs, ezetimibe, niacin):** These lower LDL and Lp(a) alongside DFPP; the interaction is generally desirable and complementary rather than harmful, allowing lower removal targets.
* **Populations who should avoid or defer the procedures:** Those with hemodynamic instability; severe cardiac disease (New York Heart Association [NYHA] Class III–IV heart failure, or recent myocardial infarction [MI, heart attack] within 90 days); active systemic infection or sepsis; severe uncorrected coagulopathy or hypofibrinogenemia; known reactions to replacement fluids; poor or unsafe venous access; and pregnancy except for a clear medical indication. Elective longevity use in any of these groups is not supported.

## Risk Mitigation Strategies

* **Prophylactic calcium management:** To prevent citrate-induced tingling, cramps, and rhythm effects, protocols supplement calcium (oral or by infusion) and slow the citrate rate; ionized calcium is checked during and after longer sessions.
* **Withhold interacting blood-pressure drugs:** To prevent bradykinin-mediated anaphylactoid reactions, ACE inhibitors are stopped for at least 24–48 hours before any negatively charged DFPP or lipoprotein-apheresis run.
* **Fibrinogen monitoring and session spacing:** To prevent bleeding from clotting-factor depletion, fibrinogen is measured before sessions in a series, kept above roughly 100 mg/dL, and treatments are spaced by 24–48 hours to allow resynthesis.
* **Prefer albumin over donor plasma:** To minimize allergic and infectious risk, 5% albumin is used as the replacement fluid rather than fresh frozen plasma whenever clotting-factor replacement is not specifically required.
* **Immunoglobulin surveillance and replacement:** To counter cumulative antibody depletion and infection risk over repeated courses, IgG is trended and immunoglobulin replacement is considered when levels fall substantially.
* **Peripheral access and conservative volumes:** To reduce catheter-related infection and hypotension, peripheral venous access is used where possible and exchange volume is limited to about 1–1.5 plasma volumes per session with careful fluid balancing.
* **Baseline screening and staged escalation:** To avoid treating unsuitable candidates, cardiac status, coagulation, calcium, and infection are screened before starting, and volumes are escalated gradually in older or frailer individuals.

## Therapeutic Protocol

* **Standard exchange dose:** Leading apheresis practitioners treat approximately one to one-and-a-half plasma volumes per session for both procedures, the range above which additional removal yields diminishing returns because extravascular factors re-equilibrate. Estimated plasma volume is calculated from weight and hematocrit.
* **Disease-course versus longevity cadence:** In established disease, sessions are typically given every other day for about five treatments; elective longevity protocols popularized by apheresis physicians such as Dobri Kiprov instead use spaced maintenance schedules — for example monthly, or a cluster of sessions repeated monthly, sometimes paired with immunoglobulin.
* **Competing approaches presented without a default:** The main choices are non-selective TPE with albumin replacement (simpler, removes everything, needs donor albumin) versus size-selective, albumin-sparing DFPP (more complex, spares albumin, targets large molecules); and within TPE, centrifugation-based versus membrane-based separation. Each has distinct trade-offs in selectivity, cost, and replacement needs, and no single approach is established as superior for longevity.
* **Attribution of approaches:** The plasma-dilution rationale traces to the Conboy laboratory; the albumin-replacement Alzheimer's protocol to the AMBAR investigators and the albumin manufacturer that funded it; DFPP/cascade filtration to Japanese groups led by Agishi and colleagues.
* **Best time of day:** Timing is not critical to efficacy; sessions are usually scheduled in the morning to allow same-day monitoring of calcium, blood pressure, and any delayed reactions.
* **Re-equilibration and rebound kinetics:** Although these are procedures rather than drugs with a half-life, removed molecules re-equilibrate from tissue and are re-synthesized over roughly 24–48 hours for antibodies and clotting factors, which is why sessions in a series are spaced accordingly rather than given daily.
* **Single versus split treatment:** Rather than splitting a dose, protocols treat a defined plasma volume in one sitting and instead adjust the number and spacing of whole sessions to reach the desired cumulative removal.
* **Genetic considerations:** Genotype guides candidate selection more than dose — high *LPA* or *LDLR* burden favors DFPP lipid targeting, while *APOE4* status is relevant when the goal is brain-related and informs expectations.
* **Sex-based considerations:** Because estimated plasma volume is lower in women for a given weight, the absolute exchange volume is individualized to avoid over-removal of clotting factors and antibodies.
* **Age-related considerations:** Older adults are treated with smaller incremental volumes, closer hemodynamic monitoring, and greater attention to cardiac reserve and access.
* **Baseline biomarker guidance:** Pre-treatment Lp(a), LDL, fibrinogen, IgG, calcium, and inflammatory markers set the targets and the safety thresholds for how aggressively to treat.
* **Pre-existing condition guidance:** The presence of familial hypercholesterolemia, autoimmune disease, or a specific removable target shapes both the choice of procedure and the realistic goal, whereas a metabolically healthy adult has a weaker rationale and should expect a smaller, less certain effect.

## Discontinuation & Cycling

* **Lifelong versus time-limited:** For disease indications such as familial hypercholesterolemia, treatment is effectively lifelong because the underlying factor keeps returning; for elective longevity use there is no established endpoint, and any schedule is inherently open-ended and experimental.
* **Withdrawal effects:** There is no physical dependence or withdrawal syndrome; stopping simply allows removed factors — cholesterol particles, antibodies, inflammatory proteins — to return toward their pre-treatment baseline over days to weeks.
* **Tapering:** No pharmacologic taper is needed; because the effect is mechanical and transient, treatment can be stopped abruptly, though those treating a lipid or antibody target should plan for the rebound to baseline.
* **Cycling for maintained effect:** Longevity protocols are inherently cyclical — because a single course does not durably lower factor levels, benefit is maintained only by repeating sessions on a schedule, which is the central practical and cost limitation of the approach.
* **Rebound planning:** For DFPP used to control Lp(a) or LDL, discontinuation should be accompanied by intensified drug therapy to prevent the treated particles from rebounding to untreated levels.

## Sourcing and Quality

* **Accredited apheresis facility:** The most important quality factor is where the procedure is done — an accredited center meeting recognized blood-banking and apheresis standards, with experienced staff and physician oversight, rather than a lightly regulated wellness clinic.
* **Replacement-fluid quality:** For TPE, the safety of the replacement matters — pathogen-reduced 5% albumin is preferred over donor fresh frozen plasma for elective use, since albumin carries far lower allergic and infectious risk.
* **Device and filter selection:** Outcomes and safety depend on appropriate hardware — the plasma-fractionator pore size in DFPP determines what is removed, and the choice between membrane and centrifugation separation affects efficiency and calcium handling; these should be matched to the target.
* **Reputable providers and transparency:** Because many longevity-oriented plasma-exchange services are commercial, quality includes transparent disclosure of protocols, evidence, costs, and conflicts of interest; established academic apheresis units and hospital-based programs offer the most rigorous oversight.
* **Not a purchased product:** Unlike a supplement, there is no bottle to vet for purity or third-party testing; quality assurance rests entirely on the facility, its staff, the fluids, and the equipment, which is why provider selection is the dominant consideration.

## Practical Considerations

* **Time to effect:** Biomarker changes — lower cholesterol particles, antibodies, and inflammatory proteins — appear immediately after a session, but any biological-age or functional effect, if real, emerges over weeks to months of repeated treatment and is not durable without ongoing sessions.
* **Common pitfalls:** The most frequent mistakes are expecting a single course to produce lasting rejuvenation, neglecting calcium supplementation, failing to stop interacting blood-pressure drugs, and pursuing unproven longevity protocols at commercial clinics without baseline screening or a defined target.
* **Regulatory status:** Apheresis devices are cleared for specific medical indications; use for general longevity or "age reversal" is off-label and not approved by regulators, and a formal regulatory warning has been issued against unproven young-plasma anti-aging products.
* **Cost and accessibility:** These are exceptionally resource-intensive interventions — a single session commonly costs on the order of one to several thousand dollars, insurers do not cover elective anti-aging use, and access is limited to specialized centers, making a repeated longevity schedule very expensive and logistically demanding.
* **Selectivity trade-off in practice:** DFPP's albumin-sparing design lowers per-session replacement cost and allergic risk, while TPE is simpler and more widely available; the practical choice often turns on local expertise and the specific target as much as on theory.

## Interaction with Foundational Habits

* **Sleep:** Indirect interaction. The procedures do not directly alter sleep architecture, but post-session fatigue and the fluid and calcium shifts can cause transient tiredness; scheduling treatments so that recovery does not disrupt a normal sleep routine is the main practical consideration.
* **Nutrition:** Direct and bidirectional interaction. Adequate protein intake supports resynthesis of albumin and clotting factors removed by treatment, good hydration reduces hypotension, and calcium and vitamin D status buffer against citrate-induced low calcium; a low-protein state worsens the albumin loss of DFPP.
* **Exercise:** Indirect interaction. Strenuous exercise immediately around a session is discouraged because fluid shifts, transient anemia, and low calcium can impair performance and safety; separating hard training from treatment days by keeping well hydrated is the practical rule, with no evidence that exchange blunts training adaptations.
* **Stress management:** Indirect interaction. The procedure itself is a physical and psychological stressor, and vasovagal reactions are partly anxiety-driven; calm pacing, familiarity with the process, and parasympathetic techniques such as slow breathing reduce fainting and improve tolerance.

## Monitoring Protocol & Defining Success

Baseline testing is performed before starting any course to establish the removable targets and the safety thresholds, and it should be reviewed with the supervising physician rather than inferred from the table alone. Ongoing monitoring follows a defined cadence — typically before each session within a series, then at roughly 1 month and every 3–6 months during maintenance, and after any adverse event.

| Biomarker | Optimal Functional Range | Why Measure It? | Context/Notes |
|-----------|--------------------------|-----------------|---------------|
| Ionized calcium | 1.15–1.30 mmol/L | Citrate lowers calcium and causes symptoms | Check during and after longer sessions; supplement proactively |
| Fibrinogen | 200–400 mg/dL (keep >100 during a series) | Depleted by exchange; low levels raise bleeding risk | Draw before each session in a course; DFPP lowers it most |
| Immunoglobulin G (IgG) | 700–1600 mg/dL | Repeated exchange depletes protective antibodies | Trend over a course; guides immunoglobulin replacement |
| LDL cholesterol | <70 mg/dL (optimal <50 if high risk) | Primary DFPP lipid-removal target | Fasting sample; pair with apolipoprotein B (ApoB, the particle-count marker) |
| Lipoprotein(a), Lp(a) | <30 mg/dL (<75 nmol/L) | Inherited atherogenic particle; key DFPP target | Genetically stable — measure once, then track treatment response |
| High-sensitivity C-reactive protein (hs-CRP) | <1.0 mg/L | General marker of inflammation/inflammaging | Do not measure during acute illness or infection |
| Albumin | 4.0–5.0 g/dL | Lost through the DFPP second filter; low levels worsen fluid shifts | Reflects nutritional status; supports safe volumes |
| Complete blood count (CBC) | Hematocrit 37–50%; platelets 150–400 ×10⁹/L | Detects anemia and platelet loss from the circuit | Baseline and periodic during a series |
| Estimated glomerular filtration rate (eGFR) | >90 mL/min/1.73 m² | Kidney function and fluid-handling safety | Baseline and periodic; lower values need caution |
| Epigenetic age clock | Younger than chronological age | Tracks the biological-age response, if any | Research-grade and noisy; interpret cautiously, not as proof |

Qualitative markers complement the labs and are tracked by the individual over a course:

* Energy and daily stamina
* Cognitive clarity and mental sharpness
* Joint stiffness and general inflammation-related discomfort
* Recovery and fatigue in the day or two after each session
* Sleep quality and overall sense of well-being

## Emerging Research

* **Flagship longevity trial (TPE):** A randomized, sham-controlled trial in adults over 50 is testing repeated therapeutic plasma exchange, with and without immunoglobulin, on epigenetic clocks and aging biomarkers ([NCT06534450](https://clinicaltrials.gov/study/NCT06534450); Phase 3, 40 participants, sham-pheresis controlled, led by Global Apheresis). Its multi-omics results have been reported by [Fuentealba et al., 2025](https://pubmed.ncbi.nlm.nih.gov/40424097/), showing biological-age rejuvenation across multiple clocks.
* **DFPP for contaminant removal:** A dedicated study is evaluating double filtration plasmapheresis specifically for reducing microplastic and nanoplastic particle burden in blood ([NCT07658443](https://clinicaltrials.gov/study/NCT07658443); enrolling by invitation, 20 participants, sponsored by Proxima Health), an emerging and unproven longevity-adjacent application.
* **Head-to-head technique comparison:** A completed randomized crossover study compared centrifugation-based against membrane-based plasma exchange for performance, efficiency, and inflammatory-cytokine clearance ([NCT06652516](https://clinicaltrials.gov/study/NCT06652516); 20 patients), informing which separation method best serves elective use.
* **Mechanistic direction (plasma dilution):** The animal basis for exchange-based rejuvenation — dilution of aged plasma with saline-albumin renewing multiple tissues — is detailed by [Mehdipour et al., 2020](https://pubmed.ncbi.nlm.nih.gov/32474458/); future work aims to identify the specific pro-aging factors whose removal drives the effect.
* **Direction that could weaken the case:** Evidence of net harm from indiscriminate removal — increased serious infections in the vasculitis synthesis by [Walsh et al., 2022](https://pubmed.ncbi.nlm.nih.gov/35217545/) — and procedural-safety questions examined by [Liu et al., 2026](https://pubmed.ncbi.nlm.nih.gov/41420369/) highlight that durability, rebound, and cumulative immune cost remain the key unresolved risks for repeated elective apheresis.

## Conclusion

Therapeutic plasma exchange and double filtration plasmapheresis are two ways of physically cleaning the blood. The first removes the whole liquid part and replaces it with a substitute; the second uses a second filter to strip out only the largest, most harmful molecules while returning the useful ones, needing little replacement fluid. Their strongest, best-proven value is removing specific harmful substances — cholesterol particles, antibodies, and inflammatory proteins — in defined medical conditions. Their use to slow aging is newer and rests on animal studies, early human biomarker trials, and the idea that thinning out age-related factors in the blood quiets damaging signals throughout the body.

The evidence for a longevity benefit is real but preliminary and mixed: biological-age markers have shifted younger in a small controlled study, yet any effect fades as the removed factors return, no lasting health outcome has been shown, and much of the supporting work comes from clinics, device makers, and companies that profit from the procedures. The risks — low calcium, bleeding, fluid shifts, allergic reactions, infection, and unknown long-term effects of repeated treatment in healthy people — are concrete and add up with each session. These are expensive, invasive, repeated procedures whose promise is genuine but unproven, and whose selective and non-selective forms suit different goals rather than one being plainly better.

**[Top](#top) - [Benefits](#expected-benefits) - [Risks](#potential-risks--side-effects) - [Protocol](#therapeutic-protocol)**