Urticaria Following B12 Injection: A Case Report

 In Bacterial/Viral Infections

Courtney Holmberg, HBSc Kin­­
Pilar Villegas, HBSc, BPS, ND

Reporting of adverse events to administered therapies is essential for further developing standards of care, practitioner education, and, most importantly, patient safety. This case report highlights a 24-year-old Caucasian female who presented with a single urticarial lesion on her chest shortly following an initial intramuscular (IM) injection of methylcobalamin, followed by 3 days of systemic pruritus. While this is not the first case report to identify such symptoms, the reaction experienced is considered rare and is often not identified when referencing methylcobalamin side effects. While the pathogenic mechanisms of adverse reactions to its use intramuscularly are not well understood, allergic responses have typically been associated with sensitivities to additives found within the injectable. However, the injection in this case report contained only 1000 mcg/mL of pure methylcobalamin in a sodium chloride solution, suggesting the reaction might likely be due to the dosage of the B12 itself, assisting in a further understanding of the mechanism of the adverse reaction. However, the primary purpose of this case report is to further aid the reader in the recognition and reporting of potential side effects associated with IM methylcobalamin injections, and to aid practitioners in educating their patients on the potential side effects associated with this therapy.


Methylcobalamin is a water-soluble B vitamin involved in the metabolism of every cell in the body, and is not naturally produced by fungi, plants, or animals. It is therefore commonly compounded into an injectable form to be used by physicians to restore nutrient depletions in the case of pernicious anemia and – more commonly by naturopathic physicians – to support fatigue, treat various neuropathies, dermatologic concerns, and cognitive function disorders.1 While vitamin B12 can be used orally, topically, intramuscularly, and intravenously, the benefits of intramuscular use include efficiency of absorption, as it bypasses the need for intrinsic factor, the cofactor necessary for its absorption into the enterocytes. Although the intramuscular use of methylcobalamin rarely presents with side effects, the most commonly associated adverse reactions present as digestive upset, pruritus, and urticaria, transitory acneiform exanthema, and, in rare cases, anaphylaxis.2 Currently, few cases of side effects have been reported in Canada, but literature review reveals, as of 2005, approximately 32 cases of acneiform or rosacea-type dermatitis developing anywhere from 10 days to 2 months following IM injections in both male and female patients of various ages, with dosages ranging from 100 to 1000 mcg/mL of hydroxycobalamin or cyanocobalamin.2,3,4 The mechanism of the reaction is not understood, but it can take up to 4 months to resolve following termination of B12 administration.3 There are no publications available for the reported diarrhea, pruritus, and urticaria listed as uncommon but possible adverse reactions, and anaphylaxis has been correlated to impurities in the B12 preparations, on which there is no published information.

Case Study

Relevant History

The patient is a 24-year old female of Caucasian descent, of average height and thin stature. She presented with a case of mild-to-moderate fatigue, generalized anxiety disorder, insomnia, and acne vulgaris on the face, upper shoulders, and mid-to-upper back, cystic in nature. The patient consumes a vegetarian diet, and has a past medical history of childhood asthma and Epstein Barr virus that resulted in temporary organomegaly. Blood work confirmed low ferritin levels, but no morphological changes to RBCs were noted. The patient has a history of oral contraceptive use, is currently taking no prescription medication, and is using Vitex agnus (1000 mg/day) to support her irregular menstrual periods.


A combination of 15 mg 5-HTP, 1 mg melatonin, and 100 mg L-theanine (1 cap
QD), was successfully used to treat her insomnia. A polysaccharide-iron complex containing 150 mg of elemental iron (1 cap QD) was given to improve iron stores and fatigue. Acupuncture (SP6, ST36, LV3, CV6, CV14, HT6, PC6, Yintang)* was completed once every 2 weeks to address the anxiety and clear dampness in the Stomach and Spleen channel, correlated to the acne. Intramuscular injections of 1000 mcg/mL methylcobalamin were then prescribed biweekly for the treatment of her fatigue, anxiety, and dietary restriction.

Adverse Reaction

The patient received her first methylcobalamin injection into her left posterior deltoid, and left the clinic 10 minutes later. She received no other treatment that day. Within 30 minutes, she reported experiencing a hyperactive and giddy mood. Within 1 hour following the injection, she developed a single, beefy-red, raised nodule superficial to her manubrium, of approximately 7 cm in diameter. At the same time, systemic pruritus developed body-wide, which took 3 days to resolve. The patient also reported sleeping very deeply that evening. There was no consumption of food shortly before or any time after the administration of the methylcobalamin, and her diet was consistent with typical intake throughout the week prior to receiving the injection. Confounding factors that may have caused the allergic response were not identified.


The patient experienced moderate anxiety towards receiving the injection, and reported a significant fear of needles. Subsequent injections (2 in total, intermittently administered 1 month apart) were administered in a supervised environment, and the patient was monitored for 1 hour post-injection, to watch for signs of reaction. Both the second and third injections were tolerated well, and were administered to the patient while she was in a non-anxious state. Due to the case’s presentation of only a single episode of urticaria following administration of B12, and coexistent complaints of anxiety, it is possible that the patient’s hyper-anxious state was a contributing cause of the reaction.

The adverse reaction leaves questions in regards to its mechanism of action, as the solution contained only saline and B12, and allergies to vitamins of any kind are extremely rare. As methylcobalamin is a methyl donor in DNA synthesis, fatty acid synthesis, and energy production, the reaction may suggest other potential deficiencies in the patient’s methylation pathways (ie, deficiencies in other essential donor receivers or recycled compounds), or a potential sensitivity to cobalamin and/or cobalt.

It is noteworthy to mention that it was considered the patient might be presenting with signs of chronic fatigue syndrome, which would categorize the adverse reaction as a symptom of the multiple chemical sensitivity associated with this condition. Symptomatically, the patient experiences relapsing fatigue greater than 6 months that is worsened by a stressful work environment, coexistent with signs of a mild depressive episode. However, the fatigue is not debilitating and the patient still regularly engages in leisure and physical activity. Therefore at this time, the likelihood of a multiple chemical sensitivity (in correlation to chronic fatigue) to be the cause of the reaction has been temporarily ruled out.


In assessing the reports of this case, it seems conclusive that the patient’s urticaria and pruritus were caused by the administration of intramuscular methylcobalamin, concomitant with the hyper-anxious state she was experiencing while it was given, as no alternative therapies or changes to the patient’s lifestyle were present at the time of administration. It is also important to note that the contents of the injectable were free of added fillers, which contradicts the majority of the research that suggests that previously reported similar adverse reactions were caused not by the B12 itself, but by the additives within the injectable. Ultimately, this case report provides further insight into the potential mechanism of action and causative factor in adverse reactions related to IM methylcobalamin, as allergies to a specific vitamin are extremely rare. Furthermore, it provides valuable insight into the importance of patient comfort and mental state when receiving semi-invasive injectable therapy. This case reports adds to the research available to both practitioners and patients in understanding the risks and anticipated side effects when administering or receiving injectable methylcobalamin therapy.

SP – spleen; ST – stomach; LV – liver; CV – conception vessel; HT – heart; PC – pericardium

Competing Interests
The author(s) declare that they have no competing interests.

Author Contributions
Pilar Villegas assisted as a clinical supervisor to the patient reported in this case, and assisted in editing the final case report. All authors read and approved the final manuscript.


Courtney Holmberg, HBSc Kin is a 4th year naturopathic intern at the Robert Schad Naturopathic Clinic, and a student of the Canadian College of Naturopathic Medicine. Prior to medical studies, she completed an honorary Bachelor of Science in kinesiology in her hometown of Sudbury, ON. Courtney has had the pleasure of providing care to members of the community at the Sherbourne Health Center, which is tailored to HIV treatment and support, and at the Brampton Naturopathic Teaching Clinic, which is the first naturopathic clinic of its kind within a hospital in Canada. As a future practitioner, Courtney aspires to minimize the disconnect between alternative and allopathic practitioners, ultimately providing patients with a thorough, educated, and well-rounded approach to addressing the root cause to their health concerns.  

Villegas_Headshot_2014Pilar Villegas, HBSc, BPS, ND graduated from the University of Toronto before completing her Doctor of Naturopathic Medicine at the Canadian College of Naturopathic Medicine. She maintains a private practice at the Vodden Medical Arts Centre in Brampton, Ontario, where she uses a variety of natural therapies to address individual health concerns. As a naturopathic physician, Pilar is dedicated to a multi-faceted approach to health care and well-being, safely combining natural therapies with mainstream medical treatments. Pilar is a clinic supervisor for senior naturopathic clinic interns at the CCNM Brampton Naturopathic Teaching Clinic, located inside the Brampton Civic Hospital, particularly focusing on individuals with chronic disease and preventative medicine.


  1. Banerjee R, Ragsdale S. The many faces of vitamin B12: catalysis by cobalamin-dependent enzymes. Ann Rev Biochem. 2003;72:209–247.
  2. Dupre A, Albarel N, Bonare JL, et al. Vitamin B12 induced acnes. Cutis. 1979;24(2):210-211.
  3. Jansen T, Romiti R, Kreuter A, Altmeyer P. Rosacea fulminans triggered by high dose vitamins B6 and B2. J Eur Acad Derm Ven. 2001;15(5):484-485.
  4. Sherertz EF. Acneiform eruptions due to “megadose” vitamins B6 and B12. Cutis. 1991;48(2):119-120.


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