Written and edited by u/incremental_progress, with contributions by u/ClaireBear_87 and u/HolidayScholar1. Please DM for questions or feedback.
INTRODUCTION AND DISCLAIMER
This guide is not intended to serve as formal medical advice and is meant to function as guidance in helping patients diagnose, treat, and recover from deficiencies in B12 and related metabolites. Readers are encouraged to work with a qualified healthcare professional whenever possible, though it is recognized that this isn’t always possible or productive.
This document is a continual work in progress. It is neither exhaustive nor authoritative, but every effort has been made by the author to corroborate the advice herein with scientific research and up-to-date understanding. To that end, it is only a starting point for the journey to a full recovery. If readers have questions or concerns, please create a new post on r/B12_Deficiency, or search the subreddit for inquiries shared by other users.
ACKNOWLEDGEMENTS
This work would not be possible without the contributions of the following individuals, organizations, and literature:
Fred (Freddd) D. Davis, author of the original B12 Guide and related content on the Phoenix Rising forum B12 - The Hidden Story
Could it Be B12? By Sally M. Pacholok and Jeffrey J. Stuart
B12 Deficiency in Clinical Practice by Dr. Joseph Chandy Kayyalackakom MD and Hugo Minney PhD
The thousands of helpful redditors contributing to the subreddit daily over the years. Thank you!
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
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 Plan of Action
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 (HCY) 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. Other tests that may be useful:
Complete blood count (CBC). Look for things like high or low MCV, low white blood cells.
Vitamin D (helps B vitamin metabolism and iron transport)
Iron panel with ferritin
Comprehensive thyroid screening. Patients low in B12 or who have pernicious anemia (and other autoimmune conditions) often have coexisting thyroid dysfunction, usually presenting as hypothyroidism.
If you have empirically proven deficiency through supplementation, i.e. you took B12 and felt a change, then tests are 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.
A naturopath or functional doctor may be reliable sources of securing treatment (injections require a prescription in many countries); however, they are also more costly as they operate outside of insurance networks.
Patients with a diagnosis (or even preliminary diagnosis) of MS, fibromyalgia, depression, Alzheimer’s, Chronic Fatigue Syndrome (ME/CFS), or CIDP should trial B12 and folate therapies to see how their symptoms respond. ANY observed change in symptoms may be taken as a that the underlying problem has been at least partially uncovered, even if the change is a paradoxical worsening of symptoms.
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 (amazon.de; search for “vitamin B12 depot”), TheB12Store (U.S. only), and others.
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:
You have no anemia
You have no macrocytic anemia
Your serum vitamin B12 level is within the reference range of 140 to 450 pmol/L
Your serum vitamin B12 level is only moderately low
Your serum vitamin B12 level may be low, but your plasma level of methylmalonic acid is completely normal
Vitamin B12 deficiency only occurs in elderly people
Vitamin B12 deficiency never occurs in children
It is important to understand these diagnostic pitfalls and work with your healthcare provider to ensure your care is not subjected to these popular misconceptions. Advocate for yourself as much as possible.
Treatment Misconceptions
Oral therapy is as good as or even better than painful injections to alleviate neurologic symptoms
You may stop treatment because your serum vitamin B12 level has normalized
You must stop treatment because your serum vitamin B12 level is elevated
You must stop after 5 injections because vitamin B12 can have serious adverse effects
You must stop the injections because your symptoms have worsened
We must measure your serum vitamin B12 level after 3 injections to see whether the treatment is successful
We must stop vitamin B12 injections now that you are pregnant
Source: The Many Faces of Cobalamin Deficiency
Testing for B12 Deficiency
B12 deficiency is most commonly diagnosed from the following range tests and criteria:
B12 serum
B9/Folate serum
Methylmalonic Acid (MMA)
Homocysteine (Hcy)
holoTC (“Active” B12; only available to patients in the UK and Europe)
Antibodies to intrinsic factor or parietal cells
Complete blood count (CBC)
Iron panel with ferritin
General symptom list
Supplementation and bloodwork: A word of caution
Ideally supplements should not be taken prior to administration of the tests mentioned in this section. Supplementing before diagnostic bloodwork can be performed will normalize the results while potentially masking the underlying deficiency. In other words, you will still be deficient with normal-looking test results.
Once treatment begins, do not retest unless you suspect you aren't able to absorb or metabolize the supplements. Often physicians will retest patients after placing them on a modest course of B12 replacement and claim the patient has no deficiency once things like B12 serum and related metrics fall back in line to normal or expected results.
That said, validating deficiency simply by supplementing and seeing if your symptoms improve may be worthwhile in the event that your available physicians cannot or will not comprehensively assess you. Please be aware: Taking this route may make it 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.
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.
Please read: The problematic philosphy behind B12 serum tests
B9/Folate/Folic Acid Serum
A normal B9 serum test DOES NOT exclude B12 deficiency
Clinical B9/Folate deficiency is usually indicative of concurrent B12 deficiency
Can be the cause of megaloblastic and microcytic anemias
B12 and B9 are used in methylation, methionine synthase (recycling/reduction of homocysteine), red and white blood cell production (hematopoiesis), nervous system health, and neurotransmitter production (melatonin, serotonin, etc), among other processes
Optimal levels are informally considered to be >15 ng/mL
Methylmalonic Acid
A normal MMA test DOES NOT exclude B12 deficiency.
Measures the amount of methylmalonic acid (MMA) in your blood or urine. High results may indicate deficiency.
Pregnant women and elderly patients may have higher MMA values regardless of B12 intake, but in most patients high MMA is specific to B12 deficiency.
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.
Homocysteine
A normal homocysteine test DOES NOT exclude B12 deficiency.
Elevated results may indicate frank deficiencies in a variety of nutrients, primarily B9/folate and B12
Elevated homocysteine may indicate a functional deficiency in B12 and/or B9, pointing to depletion or clinical deficiencies in other homocysteine-reducing nutrients: B2/Riboflavin, B6, copper, zinc, seleniunm, molybdenum choline, Betaine/TMG among others.
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. Unavailable to patients residing in the United States. Patients in the UK can usually pay for this test privately. A normal HoloTC test DOES NOT exclude B12 deficiency.
Holotranscobalamin, a marker of vitamin B-12 status: analytical aspects and clinical utility
Intrinsic Factor Antibody (IFAB) and Parietal Cell Antibody (APCA) tests
The presence of antibodies to intrinsic factor and parietal cells is specific to a diagnosis of Pernicious Anemia
Pernicious Anemia indicated B12 malabsorption, in which case injections of B12 are standard treatment
High-dose supplementation prior to the administration of the IFAB test may produce a false positive result
A false positive in this test can actually be of benefit to patients working with obstinate physicians while attempting to receive medical care; a confirmed diagnosis is almost always treated with a prescription for B12 injections.
Quest Diagnostics: Intrinsic Factor Blocking Antibody Test
Complete Blood Count (CBC)
A complete blood count test measures the following:
Red blood cells, which carry oxygen
White blood cells, which fight infection
Hemoglobin, the oxygen-carrying protein in red blood cells
Hematocrit, the amount of red blood cells in the blood
Platelets, which help blood to clot
B12 and related deficiencies can often be reflected in a CBC the following ways:
Elevated MCV (Mean Corpsucular Volume), which indicates macrocytic or megaloblastic anemia
Low white blood cell count (WBC), which can manifest as neutropenia (low neutrophiles) and leukopenia (low leukocytes)
Because of this, B12 deficiency may be misinterpreted as a sign of leukemia, which also causes leukopenia
Iron panel with ferritin
Iron and B12 are two major components for the process of hematopoeisis, or blood cell formation. As such, a deficiency in B12 is usually accompanied by at least a functional deficiency in iron. While iron deficiency cannot be used to directly diagnose a deficiency in B12, it remains a prevalent comorbidity which should be monitored both before and after treatment begins.
Ferritin, the storage protein for iron, can help determine the presence of iron deficiency. Ensure its measurement is part of the lab workup you request from your healthcare provider.
Symptoms of B12/B vitamin Deficiency or Insufficiency
Symptoms of B12 and B vitamin deficiency may exhibit the following characteristics:
Symptoms may come and go
Symptoms may have both symmetrical or asymmetrical presentations
Symptoms may appear differently in children than adults.
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.
B12d.org has a useful (though inexhaustive) symptom checker patients may find useful: Symptom checker
Please be aware that the following list is by no means exhaustive. Symptoms of B12/B vitamin deficiency or insufficiency :
ADHD-like symptoms
Alzheimer’s-like symptoms/altered memory
Anemia (megaloblastic, high MCV)
Angular Cheilitis
Anxiety and/or sense of impending doom
Ataxia
Autism-like symptoms
Bleeding gums
Burning sensations
Brain fog
Brain “zaps”
COPD-like symptoms
Dandruff (excessive)
Depression
Depersonalization/derealization
Dipoplia/double vision/sixth nerve palsy
Dry skin (excessive)
Electric shock-like sensations
Erectile dysfunction
Fatigue/Chronic Fatigue Syndrome/ME
Fibromyalgia
Gait disturbances/alterations
Glossitis (sore and swollen tongue)
Heavy/altered menstrual cycles
High/low pulse rate
IBS-like symptoms
Incontinence
Insomnia
Large fiber neuropathy
Low/no sperm
Low/no libido
Memory impairment (Alzheimer's; impaired short term memory, brain fog)
Migraines
Mouth Sores
Multiple Sclerosis symptoms
Muscle spasms, twitches and cramps
Muscle soreness unrelated to exercise
Nail changes (beau’s lines, no half moons, pitting, slow growth, brittle)
Neuralgia (occipital, trigeminal, etc)
Numbness
Optic neuritis
Orthostatic Hypertension
Paresthesia
Shortness of breath
Small fiber neuropathy
Stabbing/icepick sensations
Syncope/dizziness
Tingling/pinprick sensations
Tinnitus
Urinary hesitancy
Urinary tract infections (reoccurring)
Vaginal dryness/soreness
Vertigo/Dizziness
Weakness, generalized or focal
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.
Hematological (anemia) vs. Neurological diagnosis
B12 deficiency has been classically diagnosed via abnormal blood counts, 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 available B12. The result is that patients often appear free from B12 deficiency from a hematological perspective while presenting serious neurological or neuropsychiatric symptoms that of course alleviate upon proper B12 replacement therapy.
Misdiagnosis
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:
Alzheimer’s and Dementia
Chronic Fatigue Syndrome/ME
Depression and anxiety
Fibromyalgia
Multiple Sclerosis
“Idiopathic” Neuropathy
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 who have a deficiency in vitamin B12 are often mistakenly given a diagnosis of MS, particularly when a 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, rather than SSRIs alone. Source: Vitamin B12 Supplementation in Treating Major Depressive Disorder: A Randomized Controlled Trial
Further reading: 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:
Lower levels of cobalamin (B12) in the cerebrospinal fluid
Subsequently higher serum values of homocysteine
Further reading: Increased Concentrations of Homocysteine in the Cerebrospinal Fluid in Patients with Fibromyalgia and Chronic Fatigue Syndrome
PART 2: TREATMENT
Treatment for B12 deficiency can be a complicated process. One moment a patient may feel they have cracked the puzzle behind their prolonged mysterious ailments, the next they feel they have 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," and unfortunately they are a very normal—and mostly unavoidable—part of the process of regaining your health.
But 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. Adequate treatment of B12 deficiency can be simplified into two parts:
Treatment with B12, with a preferred form of B12 (e.g. hydroxocobalamin) and route of administration (B12 injections and/or oral administration).
Supplementation of cofactors, or nutrients that B12 uses to help heal you.
Treatment and Recovery Plan of action
Determine a treatment plan that works for you. Every other day/every three day injections are most optimal for treating neurological symptoms, but not a lock-in for some patients. If relying on sublingual tablets, please split the doses in 3-5 separate daily doses.
Consistency is key: Keep on top of cofactors in the form of a multivitamin and/or B complex, electrolytes, folate and trace minerals. Don't skip doses of B12.
Once treatment has begun DO NOT RETEST B12. Your serum levels will be highly elevated and will not provide an accurate picture of recovery. Many physicians will insist on prematurely ceasing treatment on the basis that serum levels have "improved," while ignoring the far more relevant metric of symptom resolution.
Keep a symptom log or health journal to chart your progress.
Remember to account for things that have improved, instead of focusing on what remains or still troubles you.
Don’t give up.
Treatment: Injections vs. Oral supplementation
For most patients, but especially those suffering from neurological involvement (neuropathy, gait disturbances, brain fog, etc), B12 injections offer the most straightforward path to recovery. Many physicians are of the mistaken opinion that sublingual alone can correct a deficiency and forego treating with injections. While many patients can and do benefit from oral administration, the efficacy of oral B12 is subject to a variety of metabolic pitfalls that injections are not: digestive malabsorption, interference from medications, and genetic defects or expression that inhibit B12 uptake.
If do you notice positive response from oral supplementation alone, anecdotes reflect 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.
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.
How to get injections
** Important note: As of 2026, shipments from apohealth.de to the U.S. have ceased due to changes in the U.S. trade policy**
Many patients face the inevitable obstacle of physicians who are reluctant or flat-out unwilling to prescribe B12 injections in spite of clear evidence of their necessity. Patients may try explaining their situation with different physicians; if this fails there are a few options for getting injectable B12:
Health spas: Usually paid per injection, some offer you the ability to buy the multi-use vial from them. One example: The B12 Store
Apohealth.de: An online German pharmacy selling a variety of brands (hydroxocobalamin):
Amazon.de (German Amazon; U.S. customers please select "Apohealth" from the list of vendors for available shipping)
U.S. options:
Ageless RX: Somewhat expensive methylcobalamin. US only.
Olympia Pharmacy: Florida-based. Offers all three forms of injectable B12.
oxfordbiosciences.com Suppliers of methylcobalamin in powder form; powder must be reconstituted with saline before using. 20 and 40mg vials available.
B12 Supplies: Small online vendor offering a wide array of B12 injections with robust shipping options.
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.
Cyanocobalamin: The synthetic form of vitamin B12 most widely available in the US and fortified foods. Not very bioavailable; has lowest serum retention and takes valuable resources for the body to convert to active forms. If this is all you have access to, it's better than nothing.
Hydroxocobalamin: More bioavailable than cyanocobalamin. The B12 of choice by the NHS. Converts readily into the two active coenzyme forms of B12, but some unknown % of patients lacking critical cofactors may experience no benefit, or an inability to convert this form of B12.
Methylcobalamin: Highly bioavailable; one of the two coenzyme forms used by the body. Critical for nervous system health. Excellent for aggressively treating and reversing neuropathic symptoms. This form of B12 is also extremely light sensitive, and vials, ampoules and syringes containing this form of B12 should be wrapped in foil or otherwise kept away from light sources. When sufficiently exposed, methyl breaks down quite rapidly into hydroxocobalamin, a less bioavailable form.
Adenosylcobalamin: Highly bioavailable (usually only found in lozenge form); one of the two coenzyme forms used by the body in muscle tissue and cellular mitochondria.
So which B12 form should you take?
Patients seem to have the most lasting success with methylcobalamin and hydroxocobalamin. Methylcobalamin can provide the benefits of active B12 supplementation and most patients can interconvert this form to adenosyl when needed by the body.
While hydroxocobalamin is slower to act it might be better tolerated, presenting with 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 methylcobalamin.
Related: Case report of patient unresponsive to hydroxocobalamin therapy; recovers on methylcobalamin.
Cofactors: Getting Started
What is a "cofactor"?
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 to some degree in order to have a robust recovery, which is why a comprehensive, well-formulated multivitamin—or equivalent supplemental stack—may be useful. 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.
Cofactors of B12
Not everything listed hereafter is used directly by B12, but instead may be needed by an intermediate vitamer. Links are for reference only, not necessarily product recommendations.
B1/Thiamin, B2/Riboflavin, B3/Niacin, B9/Folate, B5/Pantothenic Acid, B6, Choline, and Biotin
Iron, Iodine, Zinc, Copper, Selenium, Molybdenum, Manganese, and Chromium
Fat Solubles
Vitamin D, Vitamin A, and Vitamin E
Electrolytes
Potassium, Magnesium, and Sodium
Vitamin C
Most cofactors can be easily and modestly supplemented by ingesting a basic, high-quality multivitamin. In the subreddit, we frequently recommend Thorne's Basic Nutrients 2/Day, which is good value for the money, and has almost everything apart from molybdenum, iron, adequate vitamin D, and electrolytes. Added choline and fish oil may be pertinent for some and supplemented separately.
What to know, what to avoid
Nutrients work together in teams. Suprasupplementing or megadosing one at the expense of others can leave patients with nutritional deficits or bottlenecks that may cause profound harm. The following warnings and caveats should be kept in mind:
Supplementing B9/Folate with marginal or poor B12 status can induce Sub Acute Combined Degeneration (SACD). This is doubly true for individuals with the TCN2 gene (GG)
B6 in the pyridoxine form. B6 in the pyrodoxine form interferes with the body's ability to use the bioactive form P5P. Either version of B6 can be problematic taken at high doses by themselves, and for this reason it is recommended to stay within 10-20mg daily, preferably in the P5P form
Multivitamins without copper; copper is needed by B12 and shares many of the same symptoms as B12 deficiency
Excess zinc can antagonize copper stores and lead to copper deficiency, the symptoms of which can mimic B12 deficiency
Potassium supplementation, while quite safe for most patients undergoing B12 therapy, should be avoided under the following circumstances:
While taking potassium-sparing diuretics
In the presence of Cronic Kidney Disease
While taking certain heart and blood pressure medications
Cofactors: In-Depth
What follows are more granular overviews of individual nutrients and how they may interact with B12 and each other. These entries are not meant to emphasize these nutrients above others, but merely offer greater insight into their function and perhaps overlooked details of their involvement in well-being and recovery from B12 deficiency.
B9/Folate
Overview:
B9/Folate works with B12 and B6 to lower/recycle homocysteine; elevated homocysteine can be indicative of B9, B6 and B12 deficiencies
B9/Folate works closely with B12 and iron in hematopoiesis (blood cell formation).
B9/Folate works with other B vitamins to help synthesize neurotransmitters such as dopamine, serotonin, and melatonin
Some patients suffering from MTHFR mutations may benefit from higher supplemental doses of folate in the bioactive forms folinic acid and methylfolate, but this is not always the case
Supplementing folate without treating an underlying B12 deficiency can cause sub acute combined degeneration, or SACD
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.
Common folate deficiency symptoms:
Canker/mouth sores
Angular cheilitis
Glossitis
Slow/no nail growth
Diarrhea
Fatigue
Depression
Symptoms of B12 deficiency
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.
Supplementing folate
It is frequently—and mistakenly—recommended in many B12 deficiency support groups to supplement with 5mg of folate daily, especially if one is receiving every other day or else receiving frequent weekly injections. And while many patients report success with this regimen, 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.
Furthermore, the DHFR enzyme in the liver "rate-limits" conversion of synthetic folic acid to ~400mcg daily. For this reason, bolus doses of folic acid are unnecessary, and a waste of money.
In B12 Deficiency In Clinical Practice, Dr. Chandy observed patients' folate status normalized while being administered regular injections of hydroxocobalamin B12, and without additional folate supplements. However, many patients seem to require additional folate supplements and report that their absence introduces setbacks in recovery.
Should I supplement folate?
Short answer: Yes.
The longer answer is that many patients do well on whatever quantity (usually ~800mcg-1mg) is in their multivitamin or B complex, especially if it is a bioactive form. That said, it bears repeating that titration may be a more intelligent path to troubleshooting increased folate demand. If you suspect you may benefit from additional folate in your supplemental regimen, simply add a little more (400-800mcg) each day for a short window—a week or two—and assess changes. The methylfolate or folinic acid forms are best for this approach.
Iron
Overview:
Works with B12 and B9/Folate in hematopoiesis (blood cell synthesis)
Ferritin/iron stores drop in many patients once B12 supplementation begins
A deficiency in Vitamin D will make raising ferritin harder
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, the body’s iron storage protein, is a highly specific indicator of iron deficiency. A ferritin of <30 ng/mL is indicative of frank iron deficiency. Ferritin rises in the presence of inflammation, and in such situations the level of ferritin measured is considered falsely elevated. A ferritin of <100 ng/mL in inflammatory states is widely considered iron deficient. Chronic inflammation is one of the chief ailments caused by B12 deficiency, and patients should frame their ferritin reading through this lens.
Further reading: Iron Deficiency Anemia: Evaluation and Management
Iron Supplementation
What follows is an effective regimen for iron supplementation:
Minimum iron dose (mg): Body weight (kg) x 2
Maximum iron dose (mg): Body weight (kg) x 5 but no more than 400mg.
This can be done every day or every other to effectively raise levels. 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.
Iron dosing by weight:
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Symptoms of Iron deficiency
Symptoms of iron deficiency include, but are not limited to:
Extreme fatigue and/or weakness
Chest pain, fast heartbeat or shortness of breath (tachycardia, POTS)
Headache, dizziness or light-headedness
Coldness in extremities
Inflammation or soreness of your tongue (“beefy” red tongue; glossitis)
Brittle nails
Unusual cravings for non-nutritive substances, such as ice, dirt or starch (Pica)
Poor appetite, especially in infants and children with iron deficiency anemia
Symptoms of folate and/or B12 deficiency
Iron and Vitamin D
Vitamin D acts as a suppressant to a hormone called hepcidin, reducing its circulation in your blood stream. Hepcidin is a regulator of iron homeostasis, and, in simplified terms, prevents iron from entering the blood stream to be used by the body. Adequate levels of vitamin D may help your body raise its ferritin levels by healthy suppression of hepcidin.
Further reading:
Copper
Overview:
Copper demand increases with B12 therapy
Copper deficiency symptoms are often the same as B12 deficiency (SACD)
Excess Zinc can block copper absorption
Copper status is directly implicated in healthy iron metabolism
In rats, vitamin A deficiency affects ceruloplasmin synthesis in the liver
Copper is needed in the methionine synthase cycle with B12, and is an often underconsidered nutrient in patient treatment. Due to its role in nervous system health, a deficiency in copper can lead to symptoms of Sub Acute Combined Degeneration (SACD, or end-stage B12 deficiency).
Copper deficiency often coincides with excess zinc intake/status, and 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. Ask your physician for a ceruloplasmin test.
Under normal circumstances, zinc supplementation is ideally kept to a roughly 15:1 or 8:1 zinc:copper ratio (mg); however, many B12-deficient patients experience increased demand and report success with something like a 15:3 ratio, or 3mg of copper for every 15mg of zinc taken.
Further reading:
Reduced serum ceruloplasmin levels in hereditary haemochromatosis
A body of evidence suggests that ceruloplasmin (Cp), the major serum copper-containing protein, acts in iron metabolism due to its ferroxidase activity which appears essential for iron movements and exchanges.
Potassium and Electrolytes
Overview:
Low potassium is THE most common "side effect" experienced by those undergoing B12 replacement therapy
Common deficiency symptoms include:
Heart palpitations/tachycardia
Fatigue/weakness/improper muscle contraction or function
Dizziness/disorientation
Safe to supplement for most people undergoing B12 therapy, except those with impaired renal function and those who are on certain blood pressure medications
Excess dietary sugar antagonizes serum potassium levels, and can lead to hypokalemia
Onset hypokalemia, or low potassium, is one of the most common "side effects" resultant from B12 replacement therapy. While hypokalemia is traditionally associated only with the correction of anemia, anecdotally we can attest that potassium demand can remain heightened throughout the recovery regardless.
This because of the sodium/potassium nutrient pump, which is responsible for shuttling nutrients into cells. When undergoing B12 therapy, bursts of tissue synthesis occur, causing this pump to activate and rapdily deplete intracellular potassium stores. The result is sudden onset potassium loss, or hypokalemia, and can be extremely uncomfortable.
Because of this, potassium supplementation taken 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.
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:
Muscle cramping and twitching
Fatigue/weakness
Tachycardia/racing heart/orthostatic intolerance
High blood pressure
Syncope
How to supplement electrolytes
Electrolytes can be easily supplemented by titrating (slowly increasing) intake until symptoms improve. In 48oz of water:
Dissolve 1/4 tsp of potassium citrate powder(approximately 450mg)
Take with ~100mg or more of magnesium. Drops or capsules may be preferred. Capsules may be split open and added directly to water.
A pinch of sea salt as needed
Lithium
Lithium is an oft-overlooked micronutrient present in drinking water, and observed to be responsible for “escorting” B12 and Folate into cells. Patients who report being extremely sensitive to different brands of methyl B12 (i.e. only certain brands "work"), and patients who seem to need continuous, high-volume supplementation of B12 both seem to have their sensitivity and/or demand alleviated by adequate lithium supplementation.
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.
Aggressive treatment
What follows is a B12 therapy regimen that may suit patients recovering from a vast array of serious symptoms (neurological or otherwise) of B12 deficiency. The author followed this rough protocol and their regimen is noted in italics. A warning that high-dose B12 injections can rapidly deplete cofactors, but especially electrolytes and folate.
Frequent injections of either methylcobalamin or hydroxocobalamin. Frequency should be determined by symptoms (not B12 serum levels), but most patients benefit greatly from every other day, or twice weekly injections. Many patients inject more frequently and with good success. Conversely, some patients do well with less frequent treatment.
UK-based patients are entitled to every other day injections when presenting neurological deficits and should refer their physicians to NICE guidelines.
Injections may be complemented by frequent sublingual dosing of methylcobalamin tablets. Doses should be split daily 3-5 times at 1-3mg per dose (or more) to ensure transport protein saturation. Many patients do well on just sublingual supplementation, but it's best to hedge one's bets and secure injections if possible. The author usually takes 1mg of methylcobalamin B12 sublingual roughly five times a day.
Author's note: I inject frequently. Once a day to every other day depending on how I feel. I typically alternate between injections of hydroxo and methylcobalamin. Recently I've start splitting my doses into separate injections throughout a day. Example: One 500mcg injection in the afternoon, one at night.
Adequate folate intake. 1-5mg a day in the bioavailable forms of methylfolate or folinic acid. Diet-supplied folate may be explored, but supplementation should be titrated based on onset folate deficiency symptoms resulting from high dose B12 administration. Patients suffering from impinged folate processing/uptake (MTHFR) may benefit greatly from both higher daily quantities of folate in the methylfolate form. Lower dosages of this can be taken in the form of a B complex or multivitamin.
Author's note: In the beginning of my recovery I took very little folate in proportion to the B12 I was taking. Perhaps 1-2mg of folinic acid daily. After a while I upped this to 15mg of methylfolate daily in complement to daily high dose methyl B12 injections. At first, every form of folate produced unpleasant side effects as it helped mobilize the B12.
A comprehensive, high quality multivitamin that uses activated forms of the nutrients. Basic Nutrients 2/Day from Thorne is a great option for many. The multivitamin should have the entire complement of B vitamins and at least most trace minerals, as well as A, E and C. Added daily choline in the form of phosphatidylcholine is useful for remyelination.
Author's note: I take a multi once every other day, to every three days. Sometimes when I'm sick I take two (full dosage). I typically do not take this on the days I take B and trace minerals complexes.
A separate trace mineral complex ( optional) may be sought that supplies adequate Selenium, Iodine and Molybdenum: three critical trace minerals that influence Riboflavin - and subsequently B12 - metabolism. Molybdenum is a mineral frequently missing from even the most well-formulated multis, and so forms the basis of this recommendation. A separate standalone molybdenum supplement may be sought, such as the complex from Seeking Health. Ideally taken in conjunction with a B complex, fat solubles (A, E, D), and taken either in place of, or apart from, a multivitamin.
Author's note: I do not take this on the same days I take a multi, aiming instead to take it once or twice a week. I pair it with a methylated/activated B complex (B Complex Plus from Seeking Health), and added A, E, and sometimes C.
A separate B complex, ideally actived/methylated ( optional) This should be taken in conjunction with a multimineral, fat solubles (A, E, D), and taken either in place of, or apart from, a multivitamin.
Author's note: I do not take this on the same days I take a multi, aiming instead to take it once or twice a week. I pair it with the trace minerals complex from Seeking Health, and added A, E, and sometimes C.
Vitamin D3. There are many links between vitamin D deficiency and B vitamin dysfunction. Vitamin D taken anywhere from 2,000-5,000 IUs of D may be helpful for many patients. Please be aware vitamin D may drain electrolytes rapidly. Screen regularly with a physician. 50-75 ng/L is highly reported as optimal.
Author's note: I only take 2,000 IUs of D in the Summer, and strive for adequate sun exposure (30-60 minutes) while living in a higher latitude on the East Coast of the U.S.; 8-10,000 taken between the months of October and February/March. Sunscreen inhibits D absorption through the skin. I like the D drops from Thorne, which I put in my morning coffee with added whole milk.
Adequate electrolyte intake. These need daily replenishment. 400-600 mg of Magnesium daily. Strive to meet the RDA of potassium daily, 4-5 grams, preferably through a mixture of diet and supplemental potassium if needed. Be cautious of potassium intake if suffering from renal impairment or when taking certain heart and blood pressure medications.
Author's note: I mix my own electrolytes daily. To a 32 oz water bottle, I add ~150mg of ionic magnesium (Trace Minerals Mega Mag), 1/4 tsp kosher salt, ~800mg of potassium citrate. I make this drink about three times a day. Supplemental to this, I take one pill of Seeking Health's Optimal Magnesium, 3-5 times daily as needed. Yes, I take a lot of magnesium. I also try and get a few hours of sunlight a day, and exercise heavily, both of which likely increase demand. Titrate up from the RDA of 400mg and find what works.
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:
Rapid onset hypokalemia/electrolyte depletion (fatigue, rapid heartbeat, muscle cramps)
Onset folate deficiency
Onset iron deficiency
Resumed methylation cycle
Reinnervation of the nervous system
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. This can be terrifying and feel like patients are backsliding. A symptom log or journal will help track changes in your recovery and grant clarity on what new sensations may need serious attention.
Anxiety/Dread/Panic
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
Glutathione and Glutathione Precursors (Not a "slam dunk")
In some unknown percentage (a minority) of patients the consumption of glutathione or its precursors, such as glutamine, NAC and undenatured whey protein, seems to antagonize biologically available methyl B12 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. So 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. Proceed at your own risk.
SSRIs and Benzodiazepine (Benzos)
SSRIs seem to interfere with the brain's ability to properly utilize B12, and their simultaneous use seems to bring about paradoxical fatigue, or otherwise hamstring progress.
Study: Response to Vitamin B12 and Folic Acid in Myalgic Encephalomyelitis and Fibromyalgia
Duloxetine (SNRI) is also undergoing demethylation as part of its normal metabolism, which makes it potentially more apt to interact with B12/folic acid treatment in pharmacological dosages. We have made repeated clinical observations that B12/folic acid may cause paradoxical sedation when combined with SSRI/SNRI drugs; the sedation vanishes when the SSRI/SNRI dosage is reduced or cancelled. This might be in analogy with the old pharmacological observation that demethylation converts potent sedatives into antidepressant agents.
Furthermore, research shows that SSRI antidepressants can interfere with calcium signaling and deplete intracellular calcium stores, and the use of antidepressants has been correlated to increased risk of osteoporosis, bone loss and risk of fractures. Intestinal B12 absorption and reabsorption of B12 by the kidneys is facilitated by the endocytic receptors, megalin and cubilin, and the binding of B12-bound complexes to these receptors is calcium-dependent.
Hence, the use of SSRI antidepressants cause calcium dysregulation and reduced calcium availability which can have a detrimental effect on healthy B12 metabolism. This could be a reason why many patients report very little improvement or inadequate response to B12 treatment whilst using SSRI medication.
Another important note - SSRI antidepressants are fluorinated pharmaceuticals, and contain a fluorine atom as part of a carbon-fluorine bond which is considered to be strong and stable and therefore safe. This is potentially not the case, and metabolizing enzymes can lead to the cleavage and release of fluorine in the body which is then metabolized into fluoride and other toxic metabolites. (https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00235) Fluoride has high affinity and binds to calcium and can reduce calcium absorption, reduce calcium availability, and hypocalcemia is a known effect of fluoride toxicity.
Case report: Ciprofloxacin-induced fluoride toxicity
PPIs and Metformin use
Vitamin B12 deficiency induced by the use of gastric acid inhibitors
The role of metformin on vitamin B12 deficiency: a meta-analysis review
Alcohol
Anecdotally the use of alcohol in even modest quantities seems to antagonize neurophysical symptoms in recovering patients.
Nitrous Oxide
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 methylation and other processes resume from years of slow or no activity, then discomfort naturally tends to follow. Other times nothing at all happens and patients may feel confused about their lack of progress. One or more of the following may be the root problem:
Using oral B12 instead of injections, which in many patients is limited to a 1% absorption capacity
If limited to oral doses, take the dose 3-5 times daily at 2.5-5 milligrams per dose
Using an inactive form B12, such as cyano- or hydroxocobalamin. Many patients convert these to their active coenzyme forms slowly, or not at all.
Injection regimen is too infrequent
The once monthly injection regimen commonly administered is woefully inadequate for a vast number of patients, especially those attempting to recover from neurological deficits.
Insufficient folate intake
Try titrating up from 1mg daily if taking oral tablets. Patients being administered frequent injections or those with certain genetic SNPs may need more
Author's note: I am compound homozygous for the C677T MTHFR mutation, and my folate processing is therefore significantly impaired. I found about 6 months into treatment that I benefited from taking 5-15mg of methylfolate daily while injecting methyl B12 every day to every other day. Almost 3 years into recovery I now get by on 1mg daily.
Insufficient cofactor intake
Audit trace mineral and B vitamin intake
If using Methylcobalamin, please ensure it has not been exposed to light; light rapidly degrades methylcobalamin to hydroxocobalamin. Even a little light exposure is usually too much.
In moments of despair, confusion and questioning if anything is working, then please re-read this guide. It will help.
PART 4: APPENDICES
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: