Chelation Therapy. What can it do. What doesn't it do. State of the Knowledge January 2025.

Background

The author.

If a person writes a document purporting to describe state of the Knowledge, they should be an expert on it. Probably for the future when individuals write review type articles for the audience to appreciate how informed that article is, there should be some type of objective rating of the author's expertise. There now is such a rating system: Scholar GPS. So my rating by Scholar GPS is for my career, # 10 in MRI, # 14 in Medical Imaging, and in the top 0.05% of all scholars in all fields By my reading of the literature, I am # 1 in safety in Medical Imaging and # 1 in safety issues with GBCAs. The majority of my articles are observational and essentially all on humans (and not animals). So for humans and observations those rating would be higher still.

Chelation. What does it do.

The principle of chelation is very simple: it is picking up a molecule in the host (the person in this case) with the intention of its removal, generally by the kidneys, but with selective agents also by the hepatobiliary system. Generally when an agent shows hepatobiliary elimination it also has renal elimination as well. In the purest sense, a chelator must be safe and effective.

Metal Chelation.

Metals are virtually always cations in molecular bonding, which means positively charged, and they are positively charged by donating electrons to the other portion of the molecule. So chelators usually act as anions (molecules that receive electrons). This is true for DTPA, EDTA, DMSA and DMPS. HOPO acts in a different fashion (read my recent blog), essentially it folds over cations. DTPA therefore is a pure cation exchange chelator, it is not doing anything else, not directly affecting dopamine, serotonin, proton pumps. etc, nothing else.

Chelation. Safety.

Safety essentially is observed through the following steps. Fundamental safety/stability in test tube experiments. Safety in animals. Safety in humans. A large part of the explanation why phase steps in approval by the FDA take so long, generally 4- 10 years, to ensure that through phase 1-3 testing the agent is safe... obviously that it also does what it is purported to do. Ultimately it is after approval that a full sense of safety is achieved. So whereas in phase 3 studies, the last phase of approval for drug release, this generally involves thousands of subjects. Real world experience involves 10s of thousands to millions of subjects. Phase 4 studies are studies written on drugs, once they are available to the public through FDA approval. Other countries or country conglomerates (European Union) do their own safety testing, but do pay attention to eachother's results. Particularly most other nations/ conglomerates pay heed to FDA results, and this is true also for European Medicines Agency.

Chelation Safety. Metals.

EDTA is a molecule that has been in use for the express purpose of metal chelation for decades. It also finds its role in manufacture of many other human products, as a generic detoxifier, because it does pick up various metals. So other drugs/ products, everything from medical eye drops through to cosmetics. EDTA is used for the purpose of generic clean-up and heavy metal chelation. EDTA has been employed in 100s of thousands of individuals medically for chelation.

DTPA is a molecule that has been used for the express purpose of metal chelation also for decades. Earliest use has been for removal of radioactive heavy metals, notably Plutonium. DTPA used for the express purpose of chelation for metals in the general public has been broadly used only over the last 7 years.

DMSA and DMPS are other molecules that have been used for metal chelation for decades. The focus of their use has been on mercury, and to a lesser extent lead (DMSA).

EDTA and DTPA are administered in their active form, and eliminated in their active form. DMSA and DMPS need to be converted into active form by the liver. So the health of the liver can be compromised by these latter agents (hepatotoxicity) and also will be less effective in individuals with liver disease.

The Report.

Safety in humans.

As EDTA has been used as a pure chelator for decades and has been shown to be generally safe, it has an established presence in generic metal chelation. It also is helpful that it is readily available and relatively inexpensive.

DTPA has been used as a pure chelator for Gd (by extension other heavy metals) for less than 1 decade in common practice. Due to its newness, a number of radiologists are concerned about safety. This does however reflect a limited breadth of knowledge and understanding on their part, for the following reasons:

DTPA is the backbone of the ligand for Magnevist and Omniscan. This has been used for the dual reason: i) it binds Gd well (high stability constant), ii) has been shown for decades to be safe as a ligand for a number of medical purposes, iii) relatively easy to form the ligand-metal bond for clinical use. There have been in excess than 150 million doses of Magnevist administered, and in excess of 60 million doses of Omniscan administered world-wide, The safety of the DTPA ligand has never bee questioned per se, it has been the release of the Gd atom that has been the subject of concern and the resultant risk of developing GISF (Gad Induced Systemic Fibrosis, NSF). Omniscan is less stable than Magnevist, because the molecular side branches to the DTPA which were designed to make it nonionic, also rendered it less stable
.Millions of doses of DTPA for other purposes, such as nuclear tracers, have also been used. So an experience of >300 million doses showing safety of DTPA. Very few other drugs have shown that amount of real world usage.
Some radiologists though consider, but how often has a chelator been used to remove Gd? Both Omniscan and Optimark are manufactured with a fair amount of chelator. Omniscan with its ligand Ca-diamide, and Optimark with its, Ca-versetamide The higher safety of Optimark compared to Omniscan regarding GISF has been reported, and postulated to be due to the fact that Optimark contains more free ligand (chelator) than Omniscan; 10 % vs 5%. In fact a typical human dose of Optimark delivers the equivalent of 4 ml of chelator, which is close to the full dose of DTPA chelator for heavy metal removal (5 ml). So yes, MR ligands have been in use for concurrent chelator effect: > 60 million doses of Omniscan and > 30 million doses of Optimark.

The other question that arises is can DTPA, or reconstituted Gd-DTPA in vivo result in a hypersensitivity reaction. Based on the extensive human experience the answer is probably the risk is extremely low. There are 2 specific factors we take to offset this rare possibility: i) we do not chelate in a private clinic setting individuals with a history of severe adverse reaction, acute hypersensitivity reaction, AHR) to GBCA (a GBCA is essentially what we are recreating with chelation) and ii) we (almost) always use concurrent iv steroid with at least the first chelation, and steroids are the fundamental treatment for AHR. On occasion, when very concerned about possible acute hypersensitivity reaction we also give additional iv benadryl. Iv steroid and iv benadryl are the foundational treatments for all AHRs. The AHR symptoms I look for in the history is severe breathing difficulty after a GBCA (or other agent) and or severe cardiac arrhythmia.

As I have written in earlier blogs, the only individuals who react to DTPA are actually the individuals who need chelation with it. Some combination of heavy metal removal Flare and Heavy metal re-equilibration Flare. If you do not have heavy metal toxicity from a heavy metal that DTPA removes essentially everyone else feels nothing adverse from the iv administration. Additionally, 'normals' experience the benefit of Gd, lead, and select other heavy metal removal. So the downside in individuals without GDD or Lead Deposition Disease approaches 0, and the upside of these metals removal has some essential health benefit. As with drugs that really work, receiving too much of it in one administration,or in too short an interval, is never a good idea, even if you are 'normal' Appropriate treatment is nuanced.

Efficacy in humans.

Assessment of efficacy in humans is a simple and straightforward process, that surprisingly most individuals, including those who perform chelation, do not realize. There are two critical principles:

i) stability of the chelator with the metal of interest and ii) demonstration that it works in humans in vivo.

Stability of the chelator.

this is a lab test and one that should be documented in the literature by reliable sources.
This is generally reported as the log stability constant (also termed thermodynamic stability) DTPA with Gd is 22, EDTA with Gd is 17, so DTPA is approximately 300,000 times more stable than EDTA with Gd. To be thought of in a different way, if an MR facility used Gd-EDTA as an MR contrast agent they would be shut down by the FDA and sued by patients who received it. Gd-DTPA is a standard MR contrast agent, much less used now because there are more stable ligands that can be manufactured into an MR contrast agent. Gd-EDTA has never been used as an MR contrast agent because it is far too unstable. The exact same principle of GBCA manufacture and use, also applies to chelation, because it is the exact same principle and process: picking up Gd and holding onto it. My informed opinion, one should always use the most stable available chelator to remove a metal.

Demonstration that a chelator works in vivo.

This is a remarkably straightforward assessment that most practitioners are unaware of. If you are reading this blog then now you are aware of what to do. Obtain pre-chelation 24 hour urine for heavy metals (Doctors Data and Genova perform a panel of heavy metals) 1-3 days before chelation. Then repeat 24 hour urine for heavy metals starting with 1 hour after chelation (after the first urination post chelation). Do not administer another chelator during that 24 hour collection period. If the heavy metal goes up appreciably, then the chelator is removing the heavy metal.
Demonstration that a person is sick from that metal: a Deposition Disease state, is separate from a Storage Condition state, where the individual is not sick from the metal. This has been established in the literature for Gd, but also applies to all heavy metals. Following chelation, there is the initial period of about 1 week, in which the individual has worsening symptoms (transiently if chelation performed correctly) reflecting: heavy metal removal Flare. In the second week there should be a period of transient improvement from baseline of symptoms. With more chelation the duration and extent of improvement increases. In the third week there is recurrence of symptoms: heavy metal re-equilibration Flare, reflecting the heavy metal moving from durable reservoirs back to less durable reservoirs, to rebalance the distribution of the heavy metal. In the cases of Gd and lead this is these metals moving from bone back to soft tissue organs. This is a critical phenomenon to achieve near complete removal of the metal from the body and near complete cure. The presence of these 3 phases is essential to determine the presence of GDD, and also seems to be true for lead, and by extension probably all heavy metals. The phases may have variable intensity.
For chelators that also show hepatobiliary elimination, feces could also be studied pre- and post chelation to determine Gd removal. Despite being a gastrointestinal radiologist with MR expertise as a profession, I do not working with feces so I don't do this. This measurement is much more variable and hence unreliable than urine measurement, because feces manufacture occurs in a much less reliable timeline than urine does. Relative accuracy would require the individual not to suffer from constipation. Many individuals with GDD have constipation so Gd removal would be greatly underestimated by stool measurement. I therefore for clinical purposes would make the assumption that an agent that does have hepatobiliary removal (HOPO for example) would behave similarly to MR contrast agents that exhibit considerable hepatobiliary removal, such as eovist/primovist. About 50% is removed by kidneys and 50% by hepatobiliary, the latter reflected by presence in feces. So however much removed by kidneys I double it to reflect total Gd removal. DTPA by contrast shows near pure kidney removal, so measuring feces would be of relatively no value.

When should a chelator be used.

A chelator should be used when an individual shows the clinical features of toxicity from that metal. Prior blogs describe symptoms of GDD. Interestingly of all the heavy metals, Gd is the most straightforward since in the great majority of patients the symptoms arise within 1 week, often within hours of having received the heavy metal intravenously. The symptoms are generally consistent, and also most heavy metals have very similar symptoms. In the great majority of other heavy metal toxicities both the accrual of the heavy metal and the symptoms are more protracted and insidious. This is especially true for lead. Acute administrations of other heavy metals is uncommon, and when present generally observed with radioactive accidents or acute deliberate administrations (eg: 'dirty' bomb) or acute arsenic poisoning.

Often then determining whether a person is sick from a heavy metal or not involves observing the above 3 phases: removal, improvement, re-equilibration. If the first chelation does not show this they likely do not have the heavy metal toxicity or there is an associated condition whose symptoms supersede or overshadow those of GDD.

When should a chelator not be used.

A chelator should not be used if there is no 'reasonable' or scientific reason to suspect that it should work. A textbook could be written on this point alone. I generally restrict the use of a chelator to strict guidelines, which embody the above points. In my opinion one of the main reasons why chelation is viewed with disdain by many orthodox physicians, is that the above criteria have not been employed. I consider this valid criticism. For example, likely every American, all 350 million, have lead in their body, but the great majority are in the Storage Condition state - that is, they are not sick from it. So chelating someone and just showing they have lead in them, could be observed in 350 million people. This would bankrupt the health care system. This applies perhaps to everyone in the world, we all have lead in us. So there has to be good reason to chelate someone, unless they pay for it themselves if they are asymptomatic. So symptoms of heavy metals is a requirement.

The territory does get gray though with considering individuals with many other chronic conditions, including: autism, fibromyalgia, stiff person syndrome, lupus, ALS, multiple myeloma. Many likely do not have heavy metal toxicity, but it is not unreasonable to think that some may have toxicity as the root cause or trigger for the disease. To be convinced of the clinical value of these various entities, I, and other orthodox allopathic physicians, would require actual peer-reviewed data to show that essentially the above described points are observed in these individuals. Many of these conditions I mention here, and many more in the category of immune mediated inflammatory diseases, predisposing conditions for their development include heavy metal exposure. So the basic concept is not a stretch.

Until peer-reviewed studies show clear improvement following heavy metal removal I do not endorse wide spread use of chelation for non- direct metal toxicity causes. On an individual basis though this is an entirely different matter. If I had some condition where an underlying cause proposed for the initiation of the disease includes heavy metal toxicity, I definitely would undergo the steps I describe above. If I had lupus, stiff person disease, etc, perhaps even poorly controlled depression, I would definitely undergo at least 1 chelation with DTPA, and would do it at a center with considerable experience, for example my clinic. But this should be understood as: " who knows, maybe it will work, I have exhausted/tried other things and they have not worked well, maybe the root cause of my disease is heavy metal toxicity. It is safe, not too expensive, and at least I will get Gd, lead and some other heavy metals removed from my body, which should be a good thing". If peer-reviewed studies are performed where clear benefit is shown in a number of subjects, then I would recommend more wide spread use in the general public. So for now, the only individuals who I recommend undergo DTPA chelation are those with GDD, all should get it, and perhaps most individuals with Lead Deposition Disease.

Final Points.

I, and now others, have written enough peer-reviewed papers on GDD, that its existence is 99.999% certain. To deny this now reflects willful ignorance. To speak against its existence also reflects what I call Opinion unconfounded by knowledge.
Chelation by DTPA is presently optimal treatment for GDD. Other treatments should be used and possibly replace DTPA is they show equivalent or better log stability constant and show in vivo removal of Gd. The benefit of DTPA is also true for lead. but with less significant improvement over EDTA (EDTA and lead is 17, DTPA and Gd is 18 log stability constant).
Ancillary treatments may be useful in combination with DTPA chelation. This includes additional chelators in conjunction, eg: DMSA for mercury, HOPO to sweep up Gd loosened but not removed by DTPA. HBOT and ozone are also in this category. In my position as the world authority on GDD and DTPA chelation, I am under so much scrutiny, I cannot afford to combine other treatments that could be considered 'quackery'. So I am waiting to see peer-reviewed studies performed by others that show, in reasonable sized studies, that combining DTPA chelation with some other methodology, (all of which contain added expense and some potential for harm) before employing them myself. Ozone and HBOT are both very intriguing, but I would want to see randomly controlled studies, before I strongly advocate them or use them. So not that they are quackery, but I have to at least have a scientific basis to think they really will work well. Meeting scientific requirement for benefit has been clearly shown for DTPA. I do not discourage other ancillary approaches however, because I also want to learn from them. So HBOT I am fine with trying, sauna is good - read the limitations I describe in other blogs. LDN seems to be reasonable, and I do prescribe this in some individuals.. I strongly recommend some supplements: turmeric, chlorella, spirulina. I strongly recommend a health diet containing a broad array of anti-inflammatory foods. Also when I describe the use of HOPO I always state it in terms of what I would do in someone else's circumstance, and not tell them what they should do. So I focus on ease and cost of an oral agent like HOPO. The other point I don't mention often enough: HOPO is also removed by hepatobiliary elimination, and this should be indicated in people with renal failure. If I had GDD and poor renal function I would use HOPO, but I would also test on myself fecal Gd content pre- and post chelation as above to see if it is working. References for the value of hepatobiliary elimination additional to renal elimination are articles I have written in the peer-reviewed literature on Multihance and NSF, written between 2007-2010 as analogy.
The most common cause of 'failure' of DTPA chelation, is actually pseudo- failure. The individual has either had poorly performed chelation or has not undergone enough of well-performed chelation. I use as a yardstick that for each GBCA injection one needs 5 chelation sessions (based on the cycling of removal/ re-equilibration). But this reflects minimal complicating factors. If there are more complicating factors, especially severe ones, more chelation is needed. Common severe complicating factors are severe Multiple Chemical Sensitivity Syndrome (most individuals do have this syndrome, but those who recover quickly have mild form), complicated surgery especially back surgery in the recent history, complicated reaction to potent antibiotics, severe physical disability, such as wheelchair requirement, are the most common.,
GDD reflects for most individuals a ratio of about 50/50 immunogenicity (reactogenicity) and toxicity. Symptoms that appear generally reactogenic, such as brain fog recover relatively quickly. Symptoms in more durable locations like bone require more chelation sessions and respond relatively late, after 10 chelation sessions. Large nerve involvement also takes more time, 10 chelations at least, and this may reflect that more of the involvement is toxicity-based rather than reactogenicity - that is to say Gd actually interfering at the synaptic level, and not a simple cytokine effect. This includes facial nerve, otic nerve, optic nerve, vagus, and pudendal nerve.
During the course of appropriate chelation, when you start feeling better do not engage in intense physical activity because you are suddenly feeling better. This almost invariably will result in severe Flare. This actually underscores what I have often neglected to mention, after bone and skin, muscle is likely the third largest reservoir of Gd. Intense muscle motion pumps more Gd into the circulation, the symptom severity compounded by lactic acidosis created by substantial physical activity. The end result in significant Flare. Try also to avoid if possible potent antibiotics early in the treatment process of GDD.
Treatment of co-existent disease may be required, especially those that are common. Some co-existent disease may be chronic inactive (Lyme's disease a good example) others more likely to be active (persistent Covid, persistent Covid vaccine reaction) but effective treatment less certain. Generally chelation with DTPA and concurrent steroids shows benefit for most other diseases, as they may have a component of metal-relationship and steroids is a generic treatment for many Immune Mediated Inflammatory Diseases.
Remember the Goldilocks principle: everything in moderation. Particular attention to steroid use
The primary treatment for GDD is to never get another GBCA agent again.
At present the impact of environmental Gd, especially as a pollutant from numerous GBCA administrations performed at local MR centers is uncertain. Concern though is reasonable\
Chelation may show benefit for other co-existent diseases, but chelation for heavy metals does not serve for treatment for other conditions that the person may have (which includes the reason for getting MRI with GBCA to begin with).. So the individual with well treated GDD may still have other diseases.

Chelation May Not Work in Everyone

As a whole DTPA chelation for GDD works as well or better than most drugs for most disease. That said, there is 1-5 % of individuals with GDD that do not seem to show benefit from optimal chelation (well done DTPA chelation). In the majority of individuals with chelation failure, this simply may mean they require many more chelations to resolve than they have received to date. Some individuals however may have some underlying defect, genetic or developmental or dysregulation, the Gd has initiated, or has initiated GDD, and dragged GDD into the ruinous physical disability . This would be a pure form of the Latin quote: Abyssus Abyssum Invocat (one Hell calls forth another). Most of these people should still continue DTPA maybe at a lower dose, and search to treat the other condition that has been either triggered by or has triggered GDD, unleashing/unlocking/ releasing the hideous elements of Pandora's box. This will be addressed again in a future blog, but the most common of these unleashed conditions is severe Cutis Laxa (loose skin) and severe loss of non- diet related fat (in the face and hands most notably) observed as sunken cheeks, loss of fat in the thenar and hypothenar eminences of the hand (palm along the thumb and fifth finger) and the fingers. The opposite is quite common for fingers, swelling is common, and this is fundamentally more resolvable.. Note mild cutis laxa is common, and mild forms reversible. Large nerve pain likely reflects an inflammatory neuritis that may be separate from Gd induced neuritis, so both must be treated. I am not yet certain of the best treatment for the non-Gd cause, Gd cause is continued chelation. This is where I am looking to neurologists to determine. I am not convinced that Lyrica, amitriptyline, or nortriptyline can address then non-Gd neuritis... but I am hopefully that they or another new drug can do this.

Future and Conclusion

Removal is the critical therapy for heavy metals, and is effective. Chelation is the mechanism for removal. Other toxins unfortunately do not have the possibility for removal at this time.. Optimal chelation requires two properties: 1. high stability between chelator and heavy metal, and 2. documentation that it works in vivo. Further work to develop effective chelators for more heavy metals is necessary.

At this point I recommend for general clinical use that individuals only get chelation if they have symptoms of heavy metal toxicity, its presence can be documented, and they experience the phases of treatment response as above: especially removal Flare and re-equilibration Flare. Documentation of toxicity does require 1 properly performed chelation with urine testing.

Rarely some individuals do not appear to respond to chelation, and more research is required to discover effective ancillary treatments to co-existent other diseases.

Richard Semelka, MD