Introduction and disclaimer

This work is not intended to serve as formal medical advice, and is meant to act as guidance in helping patients diagnose, treat and recover from deficiencies in B12 and related metabolites. It is strongly encouraged to work with a qualified healthcare professional whenever possible, though it’s recognized that this isn’t always possible or productive. While this guide tries its best to offer comprehensive advice and guidance built on patient experience and medical literature, it is just a starting point. This document is a work in progress. If you see something that needs improvement, please send u/incremental_progress a DM or post in the subreddit. All other questions, please create a new post.


This work would not be possible without the contributions of the following individuals and organizations and literature:

Please Start here: The Many Faces of Cobalamin Deficiency

Speaking with one’s physician about B12 deficiency can be difficult, and the above paper (“The Many Faces of Cobalamin Deficiency) is a great starting point for helping a patient advocate for oneself, as well as learning the basics of diagnostic and treatment misconceptions surrounding B12 Deficiency.

Full text: The Many Faces of Cobalamin Deficiency

Part 1: Diagnosis (and misdiagnosis)

Diagnosis of B12 deficiency is possible through a few means. Not all are entirely reliable diagnostic tools. A “normal” serum B12 cannot exclude deficiency, and often the most reliable method of proving a deficiency is simply observing improvement of symptoms upon receiving B12 therapy.

Diagnostic Misconceptions

B12 deficient patients who find themselves at the mercy of physicians may encounter obstinance, ignorance and outright refusal for treatment. The following is a list of common misconceptions held by physicians as to why their patients have cannot be B12 deficient (Wolfenbuttel et al):

It’s important to understand these diagnostic pitfalls and work with your healthcare provider to ensure your care isn’t subjected to these popular misconceptions. Advocate for yourself as much as possible.

Diagnostic Methods (Testing)

B12 deficiency is most commonly diagnosed from the following range tests and criteria:

B12 Serum

B12 serum assays are the most commonly administered test to diagnose B12 deficiency. Unfortunately, B12 serum is the least specific test that can be administered; a patient can be severely deficient while presenting with both high or low B12, either because of some secondary disease state or due to a lack of critical cofactors (other B vitamins, trace minerals).

Please be aware: The ranges on tests administered to patients seem to vary considerably by lab, country and even physicians office.

When interpreting serum tests, 200 to 500 pg/ml is informally considered to be a gray area where a patient could be deficient despite “normal” serum values. Anything approaching the lower end of the spectrum should be treated with suspicion, but results on the higher end cannot definitively rule out deficiency. These higher serum values may be the result of what is referred to as “functional” deficiency, i.e. there is B12 available in the body, but the patient lacks other nutrients (cofactors) in order to properly metabolize it. In short, a normal B12 serum test DOES NOT exclude B12 deficiency.

Methylmalonic Acid

Per the NIH:

This test measures the amount of methylmalonic acid (MMA) in your blood or urine. MMA is a substance made in small amounts during metabolism. Metabolism is the process of how your body changes food into energy. Vitamin B12 plays an important role in metabolism. If your body doesn't have enough vitamin B12, it will make extra amounts of MMA. High MMA levels can be a sign of a vitamin B12 deficiency. Vitamin B12 deficiency can lead to serious health problems including anemia, a condition in which your blood has a lower than normal amount of red blood cells.

A normal MMA test DOES NOT exclude B12 deficiency. Please be aware: Pregnant women and elderly patients will have higher MMA values regardless of B12 intake.


Measuring homocysteine (Hcy) can help diagnose a patient with B12, B9, and B6 deficiencies; these nutrients help break down homocysteine. When a patient is deficient in one of these metabolites, elevated HCy can result. A normal homocysteine test DOES NOT exclude B12 deficiency. Cobalamin and Folate Evaluation: Measurement of Methylmalonic Acid and Homocysteine vs Vitamin B12 and Folate

HoloTC (Active B12)

The HoloTC, or holotranscobalamin, test is used to measure the metabolically active amount of B12 in a patient by measuring the B12 bound to transcobalamin. This test is generally regarded as the most specific and accurate, but is not widely available to patients residing in the United States. Patients in the UK can pay for this test to be performed privately. A normal HoloTC test DOES NOT exclude B12 deficiency.

Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility

Symptoms of B12 Deficiency

Please be aware that this list is by no means exhaustive. Furthermore, symptoms of B12 deficiency are often shared and overlap with many other nutrient deficiencies and separate pathologies, but especially other B vitamins, iron, magnesium and trace minerals. Deficiency symptoms may appear differently in children than adults.

Common symptoms of B12/B vitamin deficiency or insufficiency :

B12 is used in every system of the body from the nervous system and blood cell synthesis, to muscle tissue and the immune system. A deficient patient’s symptoms may come and go and have asymmetrical or symmetrical presentation - none of these factors can definitively rule out deficiency in and of themselves and none should be used to gatekeep a patient’s treatment.

Anemia vs. Neurological diagnosis

B12 deficiency has been classically diagnosed via abnormal blood counts, but specifically through the presence of macrocytosis (enlarged red blood cells), which is a common hematological symptom of anemia.

It’s important to understand that a patient can suffer profound neurological deterioration from B12 deficiency without presenting any classical signs of anemia or other blood abnormalities. This is perhaps in large part because of folate-fortified flour products in the U.S. and other countries. Bread, rice, cereal, and an array of prepackaged foods are all fortified with folate in the form of folic acid (the synthetic form of B9).

B12 typically works together with iron and folate for proper hematopoiesis (formation of healthy red blood cells); however, folate alone can do the “heavy lifting” for a short period while a patient suffers from a lack of proper B12 stores. The result is that patients are asymptomatic for B12 deficiency from a hematological perspective while presenting serious neurological or neuropsychiatric symptoms.

Supplementation and bloodwork

Another method for validating deficiency is simply by supplementing and seeing if a patient’s symptoms improve. Be aware: By taking this route it may be difficult to work with a physician to address a possible deficiency, because serum values are the standard diagnostic criteria physicians often rely on when attempting to make a diagnosis. Supplementing may falsely elevate a patient’s blood serum and active B12 levels, normalize other serum markers such as MMA and HCY, and result in a physician concluding no deficiency exists.


Due to B12’s involvement in a vast array of bodily processes, B12 deficiency can therefore present as a startling array of different pathologies that may be given their own distinct diagnoses while leaving the root issue unaddressed.

The following are major pathologies that are often assigned to patients suffering who are suffering from B12 deficiency:

Is it B12 deficiency or Multiple Sclerosis?

Contrary to popular belief, B12 deficiency and Multiple Sclerosis (MS) share every symptom in common, even the brain and spinal lesions used as key diagnostic criteria in making an MS-specific diagnosis. For this reason, patients with vitamin B12 deficiency are often mistakenly given a diagnosis of MS, particularly when the serum B12 test is administered and determined to be “normal” or within range, and serum homocysteine and methylmalonic acid tests either return normal or are never even administered.

For these reasons it may be prudent for all patients given a preliminary diagnosis of MS, or some other disease affecting the nervous system such as CIDP, to trial B12 and folate therapies with all cofactors to see how their symptoms may be impacted.

Further reading: Is there a link between vitamin B and multiple sclerosis?

Depression and B12/B9

Much like MS, depression is a major symptom of deficiency that is often diagnosed in patients as a singular, standalone pathology.

However, in randomized trials it has been demonstrated that both B9 and B12 are potent adjunct therapies for depression than just SSRIs alone. Vitamin B12 Supplementation in Treating Major Depressive Disorder: A Randomized Controlled Trial

Folate as adjunct therapy to SSRI/SNRI for major depressive disorder: Systematic review & meta-analysis

A retrospective analyses comparing patients with SSRI or SNRI monotherapy versus those treated with a combination of an SSRI/SNRI antidepressant and l-Methylfolate (7.5 mg or 15 mg) found adjunct therapy with l-Methylfolate in patients with MDD was more efficient, led to symptom improvement, and had fewer patients discontinue medications.

Chronic Fatigue Syndrome/ME and Fibromyalgia

According to the CDC “Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, long-term illness that affects many body systems. People with ME/CFS are often not able to do their usual activities. At times, ME/CFS may confine them to bed. People with ME/CFS have severe fatigue and sleep problems.”

Many patients with CFS/ME show excellent improvement on B vitamin supplementation, which stands to reason given the following criteria are observed in patients suffering with the disease:

Increased Concentrations of Homocysteine in the Cerebrospinal Fluid in Patients with Fibromyalgia and Chronic Fatigue Syndrome

Diagnostic Plan of Action:

  1. If you suspect you are B12 deficient, ask your physician to order a metabolic panel that includes measurements of both B12 and folate (B9), as well as MMA (methylmalonic acid) and homocysteine tests. In the UK, an active B12 test may be preferred, but does not exclude symptomatic deficiency on its own. None of these tests can definitively rule out deficiency.

  2. If you have empirically proven deficiency through supplementation, then tests are generally meaningless and will only offer falsely elevated results. If you have improved, attempt to communicate this with your physician, which may prove difficult. Consultations with multiple physicians may be necessary. Seek second, third, fourth opinions if you encounter obstinate medical professionals.

  3. A naturopath or functional doctor may be of benefit for securing treatment (injections require a prescription in many countries), but can be unreliable due to their administration of unproven treatments and methods; they can also be more costly as they operate outside of insurance networks.

  4. Patients with a diagnosis of MS, fibromyalgia, depression, alzherimer’s, Chronic Fatigue Syndrome and CIDP should trial B12 and folate therapies (with cofactors) to see how their symptoms respond. ANY observed change may be taken as a positive sign that the underlying problem has been discovered, even if the change is a paradoxical worsening of symptoms.

  5. In the end, self-treatment may be the preferred route. B12 vials for injection can be obtained from many places: Oxford Biosciences, IV/Health Spa clinics, and online stores like German Amazon (; search for “vitamin B12 depot”), TheB12Store (U.S. only), and others.

Part 2: Treatment

Treatment for B12 deficiency can be a complicated process. One moment a patient may feel they’ve cracked the puzzle behind their prolonged mysterious ailments, the next they feel they’ve gone ten steps backward in health and want to cease treatment because it has resulted in profoundly uncomfortable symptoms. We call these “Wake up symptoms,” or “start up reactions."

Invariably once B12 deficiency is identified then a path to recovery must be charted with a robust treatment regimen that aligns with getting the patient back to good health. Outlined below is a treatment plan that suits many patients recovering from a vast array of serious symptoms, neurological or otherwise, of B12 deficiency.

An aggressive treatment plan

The following regimen would be ideal for anyone with serious neurological complications from deficiency, but is well suited to treat symptoms that run the gamut.

The forms of B12

There are four types of B12. Some people need the active forms, methyl- and adenosylcobalamin - in order to recover, while others do well with hydroxo- and cyanocobalamin.

Which B12 form should you take?

Patients seem to have the most lasting success with methylcobalamin, as well as hydroxocobalamin. Methylcobalamin can provide the benefits of active B12 supplementation and most patients can interconvert this form to adenosyl when needed by the body.

So, while hydroxocobalamin is slower to act it might be better tolerated with anecdotally less start-up reactions reported by patients (though this isn’t always the case). As a caveat, there is some unknown subset of patients who cannot convert inactive cobalamins to their active forms, rendering something like hydroxocobalamin treatment useless compared to the active alternatives.

Related: Unexpected recovery of moderate cognitive impairment on treatment with oral methylcobalamin

Injections vs. Oral supplementation

For most patients, but especially those suffering from neurological involvement, B12 injections offer the mos t straightforward path to recovery. Many physicians are of the mistaken opinion that sublingual alone can correct a deficiency and forego treating with injections. This overlooks potential malabsorption issues, interference with medications and genetic defects or expression that inhibit B12 uptake.

If you notice positive response from oral supplementation alone, it is anecdotally reported that taking a dose 3-5 times daily allows for good saturation of transport proteins, which have a half-life of about 90 minutes. For best effect, leave sublingual tablets under the tongue for anywhere from 10 minutes to 30, if possible. Repeat several times daily.

Further reading with an excellent collection of data from u/continental_grip: Oral B12 vs b12 Injections

Intramuscular vs. Subcutaneous injections Patients report various response rates to either subcutaneous or intramuscular injections. Either route is fine, but what may be preferable has to be determined by the patient (or by the physician, if one is consulted).

Intramuscular injection theoretically allows for quick delivery of cobalamins to the bloodstream for tissue uptake. Proponents of subcutaneous injection prefer the slow diffusion into the bloodstream over time, perhaps allowing continual saturation of binding proteins

Cofactors: In-Depth Overview

A cofactor is any nutrient or substance that a patient needs in order to make best use of the B12 they receive during treatment. The short of it is that essentially everything is necessary, which is why a comprehensive, well-formulated multivitamin may be critical for a robust recovery. As bodily functions that have been slowed or shut down entirely suddenly restart again, it can cause a domino effect of cellular refeeding and leave a patient short on cofactor nutrients needed to rebuild tissues.

A caveat about cofactors: Nutrients all work together in teams. Suprasupplementing one nutrient above others can leave one with profound deficits that may cause profound harm or outright toxicity. The following warnings should be kept in mind:


Folate and B12 are both needed to complete the methionine synthase reaction in the human body. There are three forms of folate available: folic acid, methylfolate and folinic acid.

It is frequently recommended in many B12 support groups to supplement with 5mg of folate daily, especially if one is receiving every other day or frequent weekly injections. Many patients report success with this regimen, but it is recommended to titrate (build) upwards as one feels comfortable, and monitor for potential symptoms of folate deficiency/insufficiency that may accompany high dose B12 supplementation.

Common folate deficiency symptoms include:

Since folate and B12 are both needed for so many shared metabolic processes, there is substantial overlap in their deficiency symptoms. That said, folate seems to affect the epithelial tissues first and foremost; the skin is the largest organ in the body, and symptom presentation can be monitored easily by paying attention to new or altered skin conditions.


Once supplementation begins, a patient’s iron levels may begin to dip as it is utilized by B12 and folate to synthesize new blood cells, maintain the nervous system and normalize any hematological abnormalities. Patients, with emphasis on those who are female and menstruating (or have recently undergone childbirth), should always monitor iron levels closely with a trusted physician.

Ferritin, which is the body’s iron storage mechanism, is a highly specific indicator of iron deficiency. A ferritin of <30 ng/mL is indicative of frank iron deficiency anemia.

Iron Supplementation An effective regimen for iron supplementation as indicated by the American Hematological Society is:>

Minimum iron dose (mg): Body weight (kg) x 2

Maximum iron dose (mg): Body weight (kg) x 5 but no more than 400mg.

Though we can try and answer any questions a patient may have, the Iron Protocol facebook group is also an excellent resource for those suffering from inadequate iron levels. It’s also recommended to work with a physician to monitor iron levels periodically to avoid hemochromatosis.

Symptoms of iron deficiency include, but are not limited to:


Secondary to iron deficiency, copper deficiency, which often coincides with excess zinc intake/status, can impair iron transport in the body. If a patient has been treating their iron deficiency with little success, copper should be investigated to rule out a deficiency in this trace mineral.


Electrolytes are some of the most abundant minerals in the human body, and they need replenishment daily. In addition to regulating nerve impulses, one of their main roles is shuttling nutrients into cells via the potassium/sodium nutrient pump. This activity can cause sudden onset potassium loss, or hypokalemia, and can be extremely uncomfortable. Low potassium can be fatal.

Potassium loss upon B12 supplementation is normally associated only with the correction of anemia, as potassium is understood to be needed to form new red blood cells; however, anecdotally we can attest that additional potassium is needed throughout the recovery journey by many patients, regardless of the presence of anemia.

Potassium supplementation in tandem with a potassium-rich diet may be beneficial, but some patients, particularly those with renal disease or impairment, should avoid potassium supplements. Otherwise, supplementing the RDA of potassium is quite safe for most, but should be discussed with a physician. We recommend potassium bicarbonate (food grade) dissolved in a large glass of water.

Critical cofactors for potassium metabolism include magnesium, sodium and taurine. Chronic potassium loss is correlated with magnesium depletion, which can occur especially if one is supplementing vitamin D and its cofactors simultaneously.

The order of onset for symptoms of hypokalemia can vary per person, but appear to be consistent per individual. For example, when individual A’s potassium is low the initial symptoms may always present as tachycardia, while individual B’s might be muscle cramps/seizing.

Symptoms of potassium, magnesium and other electrolyte deficiencies include:


Lithium is an oft-overlooked micronutrient present in drinking water, and observed to be responsible for “escorting” B12 and Folate into cells.

Lithium as a Nutrient

Lithium is also important for enhancing transport of two other critically important brain nutrients, folate and vitamin B12, into cells. The transport of these factors is inhibited in lithium deficiency and can be restored by lithium supplementation.

Since vitamin B12 and folate also affect mood-associated parameters, the stimulation of the transport of these vitamins into brain cells by Li may be cited as yet another mechanism of the anti-depressive, mood-elevating and anti-aggressive actions of Li at nutritional dosage levels.

Part 3: Recovery

Recovering from deficiency can be a complex and stressful process. Depending on one’s age, how long one was deficient (and possibly a constellation of other factors) and coexisting nutrient deficiencies, recovery can take anywhere from months to years. Injections offer the maximal path to recovery for most patients, but sublingual supplementation can effectively complement these. Each patient is different and will have to figure out what works best.

It is important to keep in mind that when we heal, we tend to notice the things that haven’t improved while often overlooking all the things that have. If a patient has 15 symptoms of deficiency and five of them heal, they have a tendency to become hyper-focused on the 10 remaining symptoms even though ⅓ of their health issues have resolved.

Document your journey

For the reasons above it may be beneficial to keep a journal to document dosages of supplements, and track symptoms over the course of time. Most patients feel that B12 recovery is a very “up and down” process, and keeping a journal may reveal the overall upward trajectory of recovery even though a patient may feel like nothing is improving. Patients should pay attention to their bodies - notice changes big and small.

“Start-up” reactions (aka “wake-up symptoms” or “paradoxical reactions”)

“Reversing out,” “wake-up symptoms,” “paradoxical worsening” - the experience of temporary worsening upon receiving treatment goes by many names, and it is by far the number one complaint made by patients when treating B12 deficiency. Many patients report feeling dramatically worse, even if some of their symptoms initially heal quickly. Some patients even experience a short “honeymoon” phase where it feels as if some symptoms have gone into complete remission, only for them to come screaming back days or weeks later.

There is little in the way of medical literature that corroborates this phenomenon, but it is believed to be the result of a few processes happening at once:

When nerves “wake up” neuropathy worsens, and/or expands in scope. Regenerating nerves can be painful, and it can be difficult to know what to pay attention to in one’s recovery. Sometimes areas that weren’t an issue before can even present new or altered sensations. All of this points back to the possible need for a symptom log or journal.


Another very common experience is onset anxiety, depression and dread when first undergoing treatment. This seems to be most common with the methylcobalamin form, but patients undergoing treatment with hydroxocobalamin and cyancobalamin have reported this as well. There is no real safeguard against this and for many people it seems a necessary barrier to reclaiming their health.

These negative feelings seem to dissipate or resolve over the course of weeks to months into treatment, never to return unless a patient has relapsed and stopped their treatment course. For most patients, the onset anxiety is not dose-proportionate; 1mg of B12 produces as much anxiety as 5mg.

Some patients correlate onset anxiety with dropping potassium levels, but this association isn't entirely clear and in many patients potassium intake does not correlate to the presence of anxious feelings.

When possible, patients should communicate how they're feeling with healthcare providers and loved ones.

What to Avoid (Under development)

Glutathione and Glutathione Precursors (Potential - not a "slam dunk")

In some unknown percentage (a minotirty) of patients the consumption of glutathione or its precursors, such as glutamine, NAC and undenatured whey protein, antagonize methyl B12 stores and result in onset B12 deficiency. The mechanism for this interaction is unclear. It was first reported by Fred (Freddd) Davis in the Phoenix Rising forum, but enough patients on the subreddit have come forward corroborating this phenomenon that it warrants a word of caution.

While many patients are fine taking this group of supplements, there is seemingly no way of knowing if a patient will be in the cohort who experiences detrimental effects.

SSRIs and Benzodiazepine (Benzos)

PPIs + Metformin use

Alcohol and drug use

Troubleshooting failures

Points of failure are common in the process of treating a deficiency. Afterall, the body is trying to cope with overcoming a major biological deficit that for many patients may have been present for years or decades. As mitochondria are fed, methylation spins up and things get going, then discomfort naturally tends to follow. And other times nothing at all happens. One or more of the following may be the root problem:

Treatment and Recovery Plan of action

  1. Determine a treatment plan that works for you. Every other day/every three day injections are most optimal, but not a lock-in for some patients. If relying on sublingual tablets, please split the doses in 3-5 separate daily doses. Methylcobalamin should be preferred.

  2. Keep on top of cofactors in the form of a multivitamin and/or B complex, electrolytes, folate and trace minerals.

  3. Keep a symptom log or health journal to chart your progress.

  4. Remember to account for things that have improved, instead of focusing on what remains.

  5. Don’t give up.

In moments of despair, confusion and questioning if anything is working, then please re-read this guide. It will help.


Appendix A: Frequently Asked Questions

Appendix B: B12 Deficiency and COVID-19 infection

There is seemingly a high prevalence of patients suffering from B12 and other metabolite deficiencies post-COVID infection. Stretching back to 2021 the subreddit has been visited by numerous patients complaining of onset B12 deficiency symptoms. There is certainly something to this and patients who have contracted COVID might benefit from extra B12 and cofactor therapies.

Further reading:

The role of vitamin B12 in viral infections: a comprehensive review of its relationship with the muscle-gut-brain axis and implications for SARS-CoV-2 infection

Vitamin B12 Deficiency in COVID-19 Recovered Patients: Case Report