by Jonathan E. Prousky, ND, MSc
Chief Naturopathic Medical Officer, Professor, Canadian College of Naturopathic Medicine
1255 Sheppard Ave. East, Toronto, Ontario, M2K 1E2; 416-498-1255, ext. 235; email@example.com
Editor, Journal of Orthomolecular Medicine; firstname.lastname@example.org
Permission has been granted from the Journal of Orthomolecular Medicine for publication of this article. It was originally published in: Journal of Orthomolecular Medicine. 2010;25(2):77–88. See: http://www.orthomed.org/jom/jomsubscript.html.
Grand Winner of Townsend Letter's
2011 "Best of Naturopathic Medicine Competition"
Vitamin B12 (cobalamin) ranks among the most useful, safe, and effective orthomolecules when treating a diverse array of neuropsychiatric conditions. However, most clinicians do not consider vitamin B12 important unless the serum level is below laboratory reference ranges. Ten research reports, summarized here, indicate metabolic consequences from low-normal (but not deficient) serum B12 levels, and/or clinical improvements following therapy that markedly increased serum B12 levels. My clinical experience, along with the summarized reports, suggests that (1) serum levels of vitamin B12 not "classically" deficient by current laboratory standards are associated with neuropsychiatric signs and symptoms, and (2) clinical improvement results when serum vitamin B12 levels are optimized or markedly increased following vitamin B12 treatment. Vitamin B12's mechanisms of action are believed to include increased S-adenosylmethionine production, improved methylation, decreased plasma and brain homocysteine, compensation for inborn errors of metabolism, normalized gene expression, correction of long-latency vitamin B12 debt, and anti-inflammatory activity. Clinicians may wish to reevaluate the importance of lower-than-optimal serum vitamin B12 levels, pursue additional testing such as urinary methylmalonic acid, and consider the potential benefits of vitamin B12 treatment.
For approximately 12 years I have been using pharmacological doses of nutrients to mitigate a variety of neuropsychiatric signs and symptoms, such as anxiety, aphasias (i.e., both expressive and receptive types), ataxia, cognitive impairment, depressions, delusions, developmental delays, fatigue, hallucinations, insomnia, irritability, memory problems, mood swings, muscle weakness, neuralgias, neuropathy, obsessions, paranoid ideations, paresthesias, psychoses, and/or seizures. When treating such a diverse array of neuropsychiatric presentations, vitamin B12 (cobalamin) ranks among the most useful, versatile, safe, and effective orthomolecules at my disposal. Despite my success in observing improvements among my patients prescribed vitamin B12, recognition of vitamin B12 insufficiency remains neglected. Most clinicians do not consider vitamin B12 important unless the serum level is deficient when indicated by laboratory reference ranges. Vitamin B12 therapy continues to be viewed by many mainstream-minded clinicians as unexpected or unwarranted. The purpose of this article is therefore to show the rationality of using vitamin B12 therapeutically, even in the absence of "classical" deficiency.
What Serum Vitamin B12 Level Defines 'Classical' Deficiency?
A number of publications discuss the serum levels of vitamin B12 that reflect "classical" deficiency. According to one author, a patient is considered to be deficient in vitamin B12 when the serum vitamin B12 level is < 100 pg/ml (74 pmol/L).1 In another article, deficiency was defined as having a serum vitamin B12 level < 203 pg/ml (150 pmol/L) on 2 separate occasions, or when the serum vitamin B12 level is < 203 pg/ml (150 pmol/L) and total serum homocysteine level is > 13 µmol/L or serum methylmalonic acid > 0.4 µmol/L.2 In the province where I reside, most laboratories consider a patient to be deficient in vitamin B12 if the serum level is less than 149 pg/ml (110 pmol/L). When vitamin B12 reaches a level that would reflect "classical" deficiency, it is important to determine and rule out underlying causes (e.g., alcoholism, pernicious anemia, and vegetarian diet) and prescribe appropriate vitamin B12 replacement therapy.
Review of 10 Neuropsychiatric Research Reports about Vitamin B12
While vitamin B12 deficiency has been associated with problems in cognition, mood and psychosis, and less commonly, anxiety, patients with serum vitamin B12 levels outside of the "classical" deficient range also suffer from various neuropsychiatric signs and symptoms reflective of vitamin B12 "insufficiency."3 When these patients are given therapeutic doses of vitamin B12, their serum levels further increase and their clinical picture usually improves. I summarized 10 research reports that suggest metabolic consequences from lower-normal (but not deficient) serum vitamin B12 levels, and/or noted clinical improvements following marked increases in serum vitamin B12 levels.
Report #1: Twenty-Nine Subjects with Fatigue
Twenty-nine subjects (7 male and 22 female; mean age 41.5 years) complaining of idiopathic fatigue or tiredness completed a double-blind cross-over trial.4 The subjects were provided with intramuscular (IM) injections of hydroxocobalamin (5 mg twice weekly for 2 weeks) or identical-looking placebo injections, followed by a rest period of 2 weeks, and then a similar course of hydroxocobalamin or identical-looking placebo injections depending on treatments given during the initial 2-week trial period. Symptoms were evaluated by a daily self-rating card that assessed appetite, general feeling of well-being, fatigue, mood (i.e., level of happiness), injection response (i.e., how the injection made the subject feel), and sleep. Those subjects who received the placebo in the first 2-week period showed a favourable response to hydroxocobalamin in the second period on all measurements made. The results showed statistical significance with respect to general well-being (p = 0.006) and happiness (p = 0.032). The initial mean serum vitamin B12 level was 358.4 pg/ml (264.4 pmol/L). By the end of treatment, serum concentrations had risen to more than 2000 pg/ml (1476 pmol/L) in all but 3 of the total 29 subjects. The 3 subjects who did not have serum vitamin B12 values above 2000 pg/ml had concentrations at or above 450 pg/ml (332 pmol/L).
The authors of this study concluded that vitamin B12 has a "tonic" effect. They reasoned that the response to vitamin B12 was related to pharmacological factors such as the ability of the vitamin to penetrate into the brain or neurons, or to an influence of vitamin B12 on neural metabolism. While none of the patients had serum levels of vitamin B12 that would be considered deficient, they did respond favourably to vitamin B12 administration after their serum levels were dramatically increased by intramuscular injections.
Report #2: Sixty-One Patients: Serum vs. Brain Status of Vitamin B12
This study sought to determine to what extent vitamin B12 in the serum is a real reflection of vitamin B12 status of brain tissue.5 It comprised 3 groups of patients and 1 control group. Group 1 involved 23 patients aged 60 to 85 with dementia, group 2 involved 16 patients aged 30 to 60 with organic affective syndrome, group 3 involved 10 female patients aged 25 to 40 with postnatal depression (and complaints of neurasthenia), and the control group was 12 patients aged 25 to 50. All patients were normal hematologically, had normal liver function and kidney function tests, but did have evidence of "soft" neurologic symptoms (i.e., some combination of encephalopathy and/or polyneuropathy or neuropathy).
When the serum levels of vitamin B12 were tested, normal values (200–800 pg/ml; 148–590 pmol/L) were found in 45 of the 49 patients from groups 1 through 3. All 12 patients in the control group had serum B12 levels in the normal range. Deficient cerebrospinal fluid levels (CSF) of vitamin B12 (<5 pg/ml; <3.7 pmol/L) were found in 30 of the total 49 patients (or in 26 of the 45 patients with normal serum levels). All 12 patients in the control group had CSF levels in the normal range (>10 pg/ml; >7.4 pmol/L). Because there was a marked difference between both compartments when measured, these results indicate that a potentially treatable vitamin B12 deficiency will be overlooked in a significant portion of patients if CSF B12 levels are not included in the assessment.
Table 1: Changes in Serum and CSF Vitamin B12 Concentrations following Treatment
serum B12 (pg/ml)
CSF B12 (pg/ml)
serum B12 (pg/ml)
CSF B12 (pg/ml)
|IM injection (n = 10)
||310 (229 pmol/L) (average)
||<5 (<3.7 pmol/L) (average)
||>2400 (>1771 pmol/L) (average)
||70 (52 pmol/L) (average)
|430 (317 pmol/L)
||14 (10 pmol/L)
||2400 (1771 pmol/L)
||21 (15.5 pmol/L)
|450 (332 pmol/L)
||<5 (<3.7 pmol/L)
||>2400 (>1771 pmol/L)
||9.6 (7.1 pmol/L)
Ten patients were given 6 weeks of twice weekly IM treatment of hydroxocobalamin (1000 mcg) plus daily treatment with an oral supplement containing 50 mg zinc-DL-aspartate and 250 mg of taurine. Two patients were given 6 weeks of a daily supplement containing cyanocobalamin (0.1 mg) plus 50 mg zinc-DL-aspartate and 250 mg of taurine. Table 1 highlights the changes in both serum and CSF that resulted from vitamin B12 treatment. Treatment with IM hydroxocobalamin produced more significant increases than oral cyanocobalamin in the patients' CSF levels of vitamin B12.
In group 1 (patients with dementia), the authors speculate that zinc deficiency and its corresponding high levels of copper block the transport of B12 in the choroid plexus (and therefore, the CSF), similar to the effects of free radical chain reaction inducers like mercury, cadmium, and other neurotoxins. Group 2 (patients with organic affective syndrome), all had exposures to toxic chemicals (i.e., alcohol, industrial solvents, or halogenated hydrocarbons), which were considered causative in their neurasthenic-depressive clinical presentation. The authors speculate that these neurotoxins may block the entry of vitamin B12 into the brain, leading to CSF deficiency of the vitamin. In group 3 (patients with postnatal depression), the authors suggest that estrogens or estrogen-receptor binding chemicals (e.g., halogenated hydrocarbons) have an effect on B12 transport through the blood–brain barrier and choroid plexus, thus causing deficiency of the vitamin with the CSF.
Report #3: Sixteen Patients with Dementia and 13 Patients with Neurasthenia
In another publication by the same authors, 16 geriatric patients aged 60 through 85 years with dementia or organic affective syndrome with coexisting dementia were assessed.6 All patients had normal liver function and no gross hematological abnormalities. These patients did have signs and symptoms of polyneuropathy. Three patients had low levels of serum B12, and low levels of CSF B12. The remaining 13 patients had normal serum B12 levels (220–540 pg/ml; 162–398 pmol/L), with 9 of them also having deficient CSF B12 levels. Five patients that had normal serum levels and deficient CSF levels were given 3 months of treatment with parenteral hydroxocobalamin (unstated dose). After 3 months, they experienced clinical improvement and had a marked rise in their CSF B12 levels (50-90 pg/ml; 37–66 pmol/L).
In a second group of 13 patients (29–50 years of age) with neurasthenic symptoms, the vitamin B12 levels were assessed in both the serum and CSF. All patients had normal liver function and no gross haematological abnormalities. These patients did have "soft" neurological signs of encephalopathy and neuropathy. All 13 patients had normal serum levels of vitamin B12 (range, 280–750 pg/ml; 207–553 pmol/L), but 11 of them had deficient CSF levels (<5 pg/ml; <3.7 pmol/L). Without routine CSF analysis, the majority of these patients would not have been found to have a vitamin B12 deficiency.
The authors concluded that all patients displaying organic mental symptoms should have their CSF levels of vitamin B12 assessed. I am of the opinion that routine CSF measurements of vitamin B12 are impractical, expensive, and invasive. Perhaps another way of interpreting these results is to know that serum vitamin B12 levels within normal ranges might not reflect what is happening within the brain. To encourage normal or even optimal CSF levels of vitamin B12, marked increases in serum levels of the vitamin might be achieved through IM administration.
Report #4: Fourteen Patients with Dementia, Degenerative Types
Vitamin B12 levels in the serum and the CSF were assessed in 14 patients with dementia.7 Eleven of these patients had degenerative types of dementia, such as Alzheimer's disease, senile dementia, and Pick's disease. The serum vitamin B12 levels in all patients were normal (500–1300 pg/ml; 369–959 pmol/L). CSF levels of vitamin B12 did not correlate with severity of the dementia. After oral methylcobalamin (2000 mcg per day), neither serum or CSF levels of vitamin B12 were significantly elevated. On the other hand, when the patients were given the same oral dose plus daily IM injections of methylcobalamin (500 mcg), marked elevations occurred in both the serum and CSF compartments. This study is compelling on two fronts. First, the serum vitamin B12 ranges used in this study are much higher than those reported in other publications.1-5 Perhaps in Japan they are aware that a higher serum vitamin B12 level correlates with better health; thus, the need for a reference range that "captures" more deficient patients. Second, IM methylcobalamin was the only way to markedly increase both serum and CSF levels of vitamin B12 among the patients with dementia. Oral methylcobalamin did not appreciably increase serum and CSF levels of vitamin B12.
Report #5: Eight Patients with Personality Symptoms
Eight Patients were administered IM hydroxocobalamin to treat their personality symptoms, as assessed by the Minnesota Multiphasic Personality Inventory (MMPI).8 The patients in this trial had the following diagnoses: paranoid schizophrenia (1 patient), angioneurotic edema (1 patient), cancer prevention (1 patient), depression (2 patients), recurrent duodenal ulcer (1 patient), insomnia (1 patient), and cocaine addiction (1 patient). All of the patients were 16 years of age and older and not on any medication. They were taking a variety of supplements such as vitamins, minerals, and unsaturated fats. Their serum vitamin B12 levels were within the laboratory's normal range (115–800 pg/ml; 85–590 pmol/L). All patients, through trial and error, were given injections of hydroxocobalamin to establish ideal doses of the vitamin (doses ranged from 3000 mcg 4 times each week to 9000 mcg per day). Serum vitamin B12 levels were drawn when patients felt the greatest sense of well-being and were also drawn after the injections were discontinued for 5 to 7 days. Patients also completed the MMPI numerous times duration of the trial period. The highest serum vitamin B12 levels (average: 465,173 pg/ml; 343,205 pmol/L) were associated with MMPI patterns at or closer to normal (profile elevation average: 56.1). With lower serum vitamin B12 levels (average: 110,611 pg/ml; 81,609 pmol/L), the MMPI patterns showed much more emotional distress (profile elevation average: 67.5).
The author concluded that vitamin B12 dependency disorders are common and neglected by the medical profession because: (1) the body level of vitamin B12 needed for full biological efficiency is unknown; (2) patients might have a deficiency in transporting vitamin B12 into their tissues (low levels of transcobalamin II); and (3) a large increase in a vitamin level might be needed to "force" one or more abnormal chemical reactions to proceed normally.
Report #6: Two Patients with Sleep-Wake Disorders
Two adolescent patients with persistent sleep-wake schedule disorders responded to treatment with oral methylcobalamin.9 A 17-year-old male had hypernychthemeral syndrome (non-24-hour circadian rhythm disorder) and was unable to attend school despite trying various medications. A 15-year-old girl had delayed sleep phase syndrome (DSPS) and was similarly unable to attend school despite numerous medication trials. Both patients did not have any laboratory or clinical evidence of vitamin B12 deficiency or hypothyroidism. Improvement of their sleep-wake schedule disorders appeared immediately after the administration of high doses (3000 micrograms per day) of oral methylcobalamin. Serum concentrations of vitamin B12 during the treatment period were in the high range of normal or above normal. The female patient's serum level of B12 was 1078 pg/ml (795 pmol/L) after 2 weeks of treatment. Her baseline serum B12 level was not provided in the report. The male patient's baseline serum vitamin B12 level was 589.5 pg/ml (434.9 pmol/L) and was measured 3 more times during treatment. His last serum vitamin B12 measurement during treatment was 1161.6 pg/ml (857.03 pmol/L). For the male patient, treatment reduced the sleep-wake cycle from 24.6 hours to 24.0 hours, which was significant since his sleep-wake rhythm became entrained to the environmental 24-hour rhythm. For the female patient with DSPS, treatment decreased sleep from 10 hours to 7 hours, and the time of sleep onset normalized from 2 a.m. to midnight.
It appears that these patients responded when their serum levels increased to the high range of normal, or to levels exceeding normal. It was concluded that vitamin B12 benefited these patients either by enhancing the phase-setting effects of light through some action on the eye or retinohypothalamic tract, or by a direct phase-setting effect.
Report #7: Patient with Hypersomnia
This communication describes the successful use of oral methylcobalamin in a 32 year-old-male patient with recurrent hypersomnia of 12 years' duration.10 He would have episodes lasting a few times each year, but when the episodes increased to once every month, he was referred to a psychiatrist for further evaluation and treatment. He was prescribed 1500 mcg of oral methylcobalamin from May 1993 until October 1993. Episodes of hypersomnia stopped during this treatment period and did not recur during the 17 months of follow-up. The baseline serum B12 level was 420 pg/ml (310 pmol/L), and increased to 980 pg/ml (723 pmol/L) one month after B12 administration.
This patient's response to vitamin B12 therapy suggests that it was effective at preventing his recurrent hypersomnia, although a spontaneous remission was possible. Vitamin B12 was presumed to increase sensitivity to environmental conditions including light stimulation, thereby increasing the patient's level of consciousness and preventing episodes of hypersomnia.
Report #8: Patients with Depression
This study determined if there was an association between vitamin B12 and folate levels and the six-month treatment outcome in patients with major depressive disorder.11 Hematological indices, erythrocyte folate, and serum vitamin B12 levels were determined in 115 outpatients with major depssive disorder at baseline and again 6 months later. The 17-item Hamilton Depression Rating Scale (HDRS) was also assessed at baseline and again 6 months later. None of the patients in this study had deficient vitamin B12 levels. In the nonresponse group (n = 40), the average baseline vitamin B12 measurement was 470.5 pg/ml (347.2 pmol/L). In the partial response group (n = 34), the average baseline vitamin B12 measurement was 536.6 pg/ml (396.0 pmol/L). The full response group (n = 41) had an average baseline vitamin B12 measurement of 594.9 pg/ml (439.1 pmol/L). Higher baseline vitamin B12 levels were associated with a better outcome. There was no relationship between the hematological indices and the 6 month outcome. A positive correlation was found between both the vitamin B12 level at baseline (r = 0.39, p < 0.001) and on follow-up (r = 0.26, p = 0.006), and the decline (i.e., improvement) in the HDRS score during 6 months of treatment.
The authors concluded that the serum level of vitamin B12 may correlate with recovery from major depression. They speculated that patients might need more vitamin B12 because of lower intakes of vitamins from food or impaired assimilation from the gastrointestinal tract, higher metabolic rates, issues in monoamine synthesis, and/or the elevations of homocysteine leading to excitotoxic reactions within the brain.
Report #9: Survey of One Thousand Patients for B12 Levels
This study involved a total of 1000 individuals, aged 75 years or older living in their homes and registered with three general practitioners in Banbury, Oxfordshire, England.12 Deficient serum vitamin B12 concentrations were identified in approximately 13% (125) of study subjects and were associated with memory impairment and depression. These subjects had serum vitamin B12 levels < 180 pg/ml (133 pmol/L). After adjusting for various parameters (age, sex, and smoking), subjects with serum vitamin B12 or holotranscobalamin (holoTC) in the bottom compared with top quartiles had a twofold risk (OR = 2.17; 95% CI 1.11–4.27) and a threefold risk (OR = 3.02; 95% CI 1.31–6.98) of cognitive impairment, respectively. The mean vitamin B12 levels in the bottom 2 quartiles were 169.4 pg/ml (125 pmol/L) and 251 pg/ml (185 pmol/L) respectively. Absence of ankle tendon jerks was also associated with low vitamin B12 status.
Treatment with vitamin B12 (1000 mcg hydroxocobalamin IM) once each month for 3 consecutive months corrected the biochemical abnormalities, but had no effect on any of the clinical measurements. In older individuals without anemia, low vitamin B12 concentrations were associated with cognitive impairment and missing ankle tendon jerks.
Report #10: One Hundred and Seven Patients without Cognitive Impairment
This study involved 107 community-dwelling subjects aged 61 through 87 years without cognitive impairment at enrollment.13 It was a prospective study that assessed the relationship between markers of vitamin B12 status and brain volume loss over a 5-year period. All subjects were assessed annually by clinical examination, magnetic resonance imaging scans, and cognitive tests. Blood was drawn at baseline for measurement of serum vitamin B12, transcobalamin (TC), holotranscobalamin (holoTC), methylmalonic acid (MMA), total homocysteine (tHcy), and serum folate. Brain volume loss was greater among those with lower serum vitamin B12 and holoTC levels and higher plasma tHcy and MMA levels at baseline. Linear regression analysis showed that associations with vitamin B12 and holoTC remained significant after adjustment for various parameters (i.e., age, sex, creatinine, education, initial brain volume, cognitive test scores, systolic blood pressure, ApoE epsilon4 status, tHcy, and folate). Increased rate of brain volume loss (odds ratio 6.17, 95% CI 1.25–30.47) was associated with vitamin B12 in the bottom tertile (< 417.3 pg/ml; <308 pmol/L).
The authors concluded that low vitamin B12 status should be investigated as a treatable cause of brain atrophy and of apparent subsequent cognitive impairment in the elderly.
Vitamin B12's Purported Mechanisms of Action
My clinical experience and the above-noted reports suggest the following: first, serum levels of vitamin B12 that are not "classically" deficient by current laboratory standards are associated with neuropsychiatric signs and symptoms not limited to declines in cognitive functioning (i.e., neurological deficits), tiredness, affective disorders, psychosis, insomnia/sleep-wake disturbances, and even brain volume loss; and second, a variety of neuropsychiatric signs and symptoms improve when serum vitamin B12 levels are optimized or markedly increased following vitamin B12 treatment.
Vitamin B12 participates in the production of S-adenosylmethionine (SAM), a donator of methyl groups, and therefore it plays a decisive role in the functioning of the neuropsychiatric system. An adequate production of SAM facilitates the formation of phospholipids that comprise neuronal myelin sheaths and cell receptors, and the synthesis of monoamine neurotransmitters.14,15 Insufficient vitamin B12 would decrease the production of SAM, which would impair methylation and, consequently, impair the metabolism of neurotransmitters, phospholipids, myelin, and receptors.
Therapeutic vitamin B12 supplementation might also lower plasma and brain levels of homocysteine, which might mitigate, reverse, and potentially normalize damaged brain neurons. Elevations of homocysteine can cause neuronal injury by augmenting neuronal calcium influx, contributing to oxidative stress, activating N-methyl-D-aspartic acid channels that stimulate glutamate excitotoxicity, lowering cerebral concentrations of N-acetyl-aspartate, and inducing cerebral mitochondrial dysfunction.16-19
Four interrelated mechanisms for vitamin B12's therapeutic benefits were highlighted by Kaplan et al. when delineating the potential reasons by which vitamins and minerals influence mood.20 Supplemental vitamin B12 might correct for inborn errors of metabolism. Pauling, Newbold, and Ames reasoned that micronutrients, which would include vitamin B12, are required to increase coenzyme concentrations and therefore correct defective enzymatic activity by enabling abnormal chemical reactions to proceed normally.8,21,22 Another mechanism involves the correction of deficient methylation. Methylation deficiency has been described in the literature to be responsive to IM injections of vitamin B12 (as cyanocobalamin) in a patient with schizophrenia, and has been identified as being part of the pathogenesis of schizophrenia.23,24 A further mechanism involves the correction of altered gene expression. It is well established that nutrients influence genetic expression. Genotyping identified transcobalamin II (TCNII) gene variants among community-dwelling older women.25 These gene variants lead to decreased vitamin B12 availability (i.e., tissue vitamin B12 deficiency), leading to reduced energy metabolism, and contribute to frailty pathology. It is possible that TCNII gene variants exist among individuals presenting with various neuropsychiatric signs and symptoms. Vitamin B12 supplementation might modify the TCNII genes (and possibly other vitamin B12 dependent genes) that depend on sufficient vitamin B12 levels and therefore modify the phenotypic expression of the implicated genes.
An additional mechanism indicates that micronutrients might resolve long-latency deficiency diseases. It has been argued that many chronic diseases (e.g., cancer, cardiovascular disease, and central nervous system degeneration) are long-latency effects.26 Kaplan et al. cite the development of depression and bone density loss as an example of a long-latency disease since it occurs many years following inadequate calcium absorption.20 With respect to vitamin B12, perhaps some patients who present with neuropsychiatric signs and symptoms do so after years of vitamin B12 debt. This might explain why a disproportionate number of patients with clinical features of vitamin B12 debt tend to be older as opposed to younger. However, I have seen young patients with clinical features of vitamin B12 debt as well. This mechanism is questionable since early childhood neuropsychiatric symptoms can result from suboptimal vitamin B12 status (e.g., due to dietary factors, gastrointestinal factors, and/or some other reasons), and would therefore be a short- and not long-latency effect.
One more mechanism that might account for some of vitamin B12's benefits has to do with its purported anti-inflammatory effects. It is known that vitamin B12 debt might lead to neurologic damage, since deficiency in rats has been associated with increased tumor necrosis factor-alpha (TNF-alpha) and decreased epidermal growth factor (EGF), an important neurotrophic agent.27 Supplemental vitamin B12 (in the form of methylcobalamin) has been shown in vitroto blunt inflammatory cytokine production in patients with rheumatoid arthritis.28 While preliminary, vitamin B12 might reduce inflammation by modifying the levels of TNF-alpha and EGF within the body and perhaps within the brain as well.
Table 2 highlights the biochemical reasons (underlying mechanisms) for vitamin B12's therapeutic effectiveness.
Table 2: Vitamin B12's Purported Mechanisms of Action
1. Increases S-adenosylmethionine, which participates in the formation of phospholipids that comprise neuronal myelin sheaths and cell receptors, and the formation of monoamine neurotransmitters
2. Lowers plasma and brain levels of homocysteine, which might mitigate, reverse, and potentially normalize damaged brain neurons
3. Corrects inborn errors of metabolism
4. Corrects deficient methylation processes
5. Corrects altered gene expression
6. Resolves long-latency vitamin B12 debt (?)
7. Has anti-inflammatory properties
Evaluating Patients with Neuropsychiatric Signs and Symptoms
In addition to hypothesis-driven physical examination, all patients presenting with neuropsychiatric signs and symptoms should have their fasting serum vitamin B12 levels tested. I created/adapted an evaluation scheme by drawing from my clinical experience and combining a published guideline with vitamin B12 laboratory reference ranges from several medical laboratories in Ontario.1 Table 3 presents a diagnostic process to consider when reviewing serum vitamin B12 levels.
With respect to Table 3, urinary methylmalonic acid (uMMA) testing can identify tissue vitamin B12 deficiency when serum levels are considered normal by conventional laboratory standards.29-31 While I have not found a large percentage of patients to have elevated uMMA levels (reflecting tissue vitamin B12 deficiency), I routinely requisitioned this test to investigate this possibility.
Table 3: Evaluating Serum Vitamin B12 Results in Patients with Neuropsychiatric Signs and Symptoms
|Serum Vitamin B12 Result
|| Further Testing
|< 149 pg/ml
|Search for underlying causes, which might include antiparietal, anti-intrinsic factor antibody testing, gastroscopy and rule out malabsorption
||Treat with vitamin B12
|Urinary methylmalonic acid to identify tissue vitamin B12 deficiency
||Empiric trial with vitamin B12
|> 400 pg/ml
(> 295 pmol/L)
||Empiric trial with vitamin B12
Prior research does support a clinical trial of vitamin B12 in patients with neuropsychiatric signs and symptoms.32 Hydroxocobalamin and methylcobalamin are the forms of vitamin B12 that I administer for therapeutic purposes. I tend to exclusively rely on methylcobalamin when a patient presents with neurologic abnormalities, and use a combination of methyl and hydroxy forms when neurologic and psychiatric abnormalities are present. There is evidence supporting the use of methylcobalamin for a variety of neurological diseases, such as Alzheimer's disease, Bell's palsy, and multiple sclerosis.33-36 While there is proof that an oral dose of cyanocobalamin (1000 mcg daily for 3 years) can effectively treat patients with pernicious anemia, my clinical experience has shown it to be inferior to the other forms of vitamin B12.37 A report did demonstrate a greater rise in the baseline serum vitamin B12 level following parenteral hydroxocobalamin (106% increase) compared with parenteral cyanocobalamin administration (78% increase).38 Parenteral forms of vitamin B12 outperformed oral (43% increase) and sublingual (34% increase) cyanocobalamin in the same study. Methylcobalamin is believed to be effective whether it is administered parenterally or orally because positive clinical results have been reported irrespective of the method of administration.35
I have not observed any side effects or toxicity from methylcobalamin. The only rare side effect from hydroxocobalamin is an acneiform exanthema, particularly in women.39 The lesions consist of loosely disseminated small papules or papulopustules on the face, the upper parts of the back, and chest, and can spread to the upper arm. They go away within a week after discontinuing regular injections and/or oral supplementation.
Although IM injections are clinically more efficacious than oral forms of vitamin B12, the frequency, dose, and method of administration must be individualized to each patient. Some patients respond clinically to 1000 mcg IM of either form each month, while other patients require 5000 mcg twice each week of IM methylcobalamin to control their symptoms. A trial-and-error approach based on patient response, willingness to comply with regular IM injections, and/or the capacity to self-administer injections is needed when using vitamin B12 therapeutically.
Here, I present 2 cases from my clinical practice showing the benefits of maintaining high serum levels of vitamin B12. Written consent was obtained from these patients for publication of this report.
A 47-year-old male presented to my private practice several years ago. He first started having anxiety symptoms 20 years ago coupled with obsessive-compulsive behaviors. He would often drive to and from locations worrying about hitting someone, or that he had in fact hit someone with his car. He would also worry excessively about having cancer and other diseases. His symptoms became so bad that at 34 years of age he had a nervous breakdown. The patient was on Zoloft (sertraline hydrochloride) at a dose of 75 mg daily and had used antidepressants for 13 years. The Zoloft, according to his report, improved his symptoms by about 80%. He had an initial Beck Anxiety Inventory (BAI) score of 28, placing him in the "severe anxiety" category. All laboratory tests were normal (red blood cell magnesium and folate, ferritin, fasting plasma glucose, and complete blood count). His serum vitamin B12 result was above normal at 343 pg/ml (253 pmol/L), but not optimal by my standards.
On December 11, he was given an intramuscular injection of 5000 mcg of vitamin B12 (methylcobalamin). He was also prescribed 5 mg of oral methylcobalamin to take daily. On January 22, he had his second follow-up appointment. He could not believe the improvement. He was able to reduce the Zoloft to 50 mg, and noted that his anxiety seemed to be well controlled. His BAI score decreased to 11 (mild anxiety). The patient's plan was to wean off the Zoloft over the next few months.
On March 28, another serum vitamin B12 was test was done. His level increased to greater than 1762 pg/ml (1300 pmol/L). He returned for another follow-up on September 17 and reported having had a stressful summer. Even though he had plenty of worries (selling his home, moving to a new home, and trying to have a baby), he was able to wean himself off his medication during the month of May. This was the first time in 13 years that he was able to discontinue mainstream antidepressant medication and feel relatively normal and symptom free.
This 49-year-old female patient presented to my clinical practice. She described herself as being "Type A" while working in a high-pressure advertising position for the past 23 years. Two years prior to my consultation, she had an episode wherein words became blurry on her computer screen, she could not grab things with her hands, and she could not speak. She recalled that during the episode, stop signs appeared backwards and she could not even remember her dog's name. A neurologist diagnosed the patient as having had a transient ischemic attack (TIA), even though the episode lasted for a couple of days. She recounted similar albeit smaller episodes a few months prior to my consultation. A computed tomography scan revealed no space-occupying lesion or focal abnormalities, and the electroencephalogram result was normal. Physical examination revealed no abnormalities or neurologic deficits. She had difficulty remembering 3 words that I asked her to repeat 5 minutes later. I explained to the patient that I wasn't sure about her diagnosis. I mentioned that her vitamin B12 status might be implicated in the genesis of her neurologic symptoms.
The patient's serum vitamin B12 result was 290 pg/ml (214 pmol/L) and not optimal according to my standards. I administered an IM injection of 1000 mcg hydroxocobalamin and told the patient to return in 10 days for another injection. A second injection was given, but this time the dose was increased to 1500 mcg. About 1 month after the initial consultation (end of February), the patient returned for a third injection. She felt about 80% better, and noticed that she could remember events and articulate her thoughts better. Other symptoms remitted as well, which included numbness, tingling, and dizziness. She was given another injection of 1500 mcg during the visit. She returned in early March for a follow-up visit. She maintained her 80% improvement level and was given another injection at 1000 mcg of hydroxocobalamin. She also brought serum vitamin B12 results from another clinician, and her level increased to greater than 2000 pg/ml (1476 pmol/L) since commencing treatment.
About 1 month later, in early April, the patient returned for another visit. She noticed a regression of her symptoms by about 20%, as her speech issues were returning. I gave the patient an injection of 1500 mcg (1000 mcg hydroxocobalamin and 500 mcg methylcobalamin). Two weeks later, she came in for another injection and felt back to her original improvement level. Since that time, the patient comes every 2 weeks and feels that her symptoms are kept at bay from receiving IM injections of vitamin B12. It should also be noted that the patient had symptoms of mild anxiety when she first presented. She scored a 14 on the BAI, placing her in the "mild anxiety" category. About 5 weeks after vitamin B12 therapy commenced, her BAI score decreased to a 6, which is essentially normal.
Clinicians may wish to reevaluate the importance of lower-than-optimal serum vitamin B12 levels, pursue additional testing such as uMMA, and consider the potential benefits of vitamin B12 treatment.
1. Oh RC, Brown DL. Vitamin B12 deficiency. Am Fam Physician. 2003;67:979–986,993–994.
2. Andrès E, Loukili NH, Noel E, et al. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ, 2004;171:251–259.
3. Becker M, Axelrod DJ, Oyesanmi O, et al. Hematologic problems in psychosomatic medicine. Psychiatr Clin North Am. 2007;30:739–759.
4. Ellis FR, Nasser S. A pilot study of vitamin B12 in the treatment of tiredness. Br J Nutr. 1973;30:277–283.
5. van Tiggelen CJM, Peperkamp JPC, Tertoolen JFW. Vitamin B12 levels of cerebrospinal fluid in patients with organic mental disorders. J Orthomolec Psych. 1983;12:305–311.
6. van Tiggelen CJM, Peperkamp JPC, Tertoolen JFW: Assessment of vitamin B12 status in CSF. Am J Psychiatry. 1984;141:136–137.
7. Mitsuyama Y, Kogoh H: Serum and cerebrospinal fluid vitamin B12 levels in demented patients with CH3-B12 treatment – preliminary study. Jpn J Psychiatry Neurol. 1988;42:65–71.
8. Newbold HL: Vitamin B12: placebo or neglected therapeutic tool. Med Hypotheses. 1989;28:155–165.
9. Ohta T, Ando K, Iwata T, et al. Treatment of persistent sleep-wake schedule disorders in adolescents with methylcobalamin (vitamin B12). Sleep. 1991;14:414–418.
10. Yamada N: Treatment of recurrent hypersomnia with methylcobalamin (vitamin B12): a case report. Psychiatry Clin Neurosci. 1995;49(5–6):305–307.
11. Hintikka J, Tolmunen T, Tanskanen A, et al. High vitamin B12 level and good treatment outcome may be associated in major depressive disorder. BMC Psychiatry. 2003;3:17.
12. Hin H, Clarke R, Sherliker P, et al. Clinical relevance of low serum vitamin B12 concentrations in older people: the Banbury B12 study. Age Ageing, 2006;35:416–422.
13. Vogiatzoglou A, Refsum H, Johnston C, et al. Vitamin B12 status and rate of brain volume loss in community-dwelling elderly. Neurology. 2008;71:826–832.
14. Karakula H, Opolska A, Kowal A, et al. Does diet affect mood? The significance of folic acid and homocysteine. Pol Merkur Lekarski. 2009;26:136–141.
15. Hutto BR: Folate and cobalamin in psychiatric illness. Compr Psychiatry. 1997;38:305–314.
16. Ho PI, Collins SC, Dhitavat S, et al. Homocysteine potentiates beta-amyloid neurotoxicity: role of oxidative stress. J Neurochem. 2001;78:249–253.
17. Ho PI, Ortiz D, Rogers E, et al. Multiple aspects of homocysteine neurotoxicity: glutamate excitotoxicity, kinase hyperactivation and DNA damage. J Neurosci Res. 2002;70:694–702.
18. Bisschops RH, van der Graaf Y, Mali WP, et al. Elevated levels of plasma homocysteine are associated with neurotoxicity. Atherosclerosis. 2004;174:87–92.
19. Zieminska E, Matyja E, Kozlowska H, et al. Excitotoxic neuronal injury in acute homocysteine neurotoxicity: role of calcium and mitochondrial alterations. Neurochem Int. 2006;48(6–7):491–497.
20. Kaplan BJ, Crawford SG, Field CJ, et al. Vitamins, minerals, and mood. Psychol Bull. 2007;133:747–760.
21. Pauling L. Orthomolecular psychiatry. Varying the concentrations of substances normally present in the human body may control mental disease. Science. 160:265–271.
22. Ames BN, Elson-Schwab I, Silver EA: High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding (increased Km): relevance to genetic diseases and polymorphisms. Am J Clin Nutr. 2002;75:616–658.
23. Regland B, Johansson BV, Gottfries CG: Homocysteinemia and schizophrenia as a case of methylation deficiency. J Neural Transm Gen Sect. 1994;98:143–152.
24. Regland B, Johansson BV, Grenfeldt B, et al. Homocysteinemia is a common feature of schizophrenia. J Neural Transm Gen Sect. 1995;100:165–169.
25. Matteini AM, Walston JD, Bandeen-Roche K, et al. Transcobalamin-II variants, decreased vitamin B12 availability and increased risk of frailty. J Nutr Health Aging. 2010;14:73–77.
26. Heaney RP: Long-latency deficiency disease: insights from calcium and vitamin D. Am J Clin Nutr. 2003;78:912–919.
27. Miller J: Vitamin B12 deficiency, tumor necrosis factor-a, and epidermal growth factor: a novel function for vitamin B12? Nutr Rev. 2002;60:142–151.
28. Yamashiki M, Nishimura A, Kosaka Y: Effects of methylcobalamin (vitamin B12) on in vitro cytokine production of peripheral blood mononuclear cells. J Clin Lab Immunol. 1992;37:173–182.
29. Matchar DB, Feussner JR, Millington DS, et al. Isotope-dilution assay for urinary methylmalonic acid in the diagnosis of vitamin B12 deficiency. Ann Intern Med. 1987;106:707–710.
30. Normal EJ, Morrison JA: Screening elderly populations for cobalamin (vitamin B12) deficiency using the urinary methylmalonic acid assay by gas chromatography mass spectrometry. Am J Med. 1993;94:589–594.
31. Donaldson MS: Metabolic vitamin B12 status on a mostly raw vegan diet with follow-up using tablets, nutritional yeast, or probiotic supplements. Ann Nutr Metab. 2000;44:229–234.
32. Delva MD: Vitamin B12 replacement. To B12 or not B12? Can Fam Physician. 1997;43:917–922.
33. Ikeda T, Yamamoto K, Takahashi K, et al. Treatment of Alzheimer-type dementia with intravenous mecobalamin. Clin Ther. 1992;14:426–437.
34. McCaddon A, Hudson PR: L-methylfolate, methylcobalamin, and N-acetylcysteine in the treatment of Alzheimer's disease-related cognitive decline. CNS Spectr. 2010;15(1 Suppl 1):2–5; discussion 6.
35. Methylcobalamin. Altern Med Rev. 1998;3:461–463.
36. Kira J, Tobimatsu S, Goto I: Vitamin B12 metabolism and massive-dose methyl vitamin B12 therapy in Japanese patients with multiple sclerosis. Intern Med. 1994;33:82–86.
37. Berlin H, Brante G, Pilbrant A: Vitamin B12 body stores during oral and parenteral treatment of pernicious anemia. Acta Med Scand. 1978;204:81–84.
38. Sohler A, Pfeiffer CC, Kowalski T: Effectiveness and route of administration of vitamin B12. Int Clin Nut Rev. 1989;9:64–65.
39. Werbach MR, Moss J. Acne vulgaris. In: Textbook of Nutritional Medicine. Tarzana, CA: Third Line Press Inc.; 1999:67–70.
Jonathan E. Prousky, ND, MSc
Chief Naturopathic Medical Officer, Professor, Canadian College of Naturopathic Medicine
1255 Sheppard Ave. East, Toronto, Ontario, M2K 1E2;
416-498-1255, ext. 235; email@example.com
At the Canadian College of Naturopathic Medicine, Dr. Prousky's primary responsibility is the delivery of safe and effective naturopathic medical care in his role as the Chief Naturopathic Medical Officer, a position he has held since 2003. His private practice focus is on optimizing mental and neurological health with nutrition and botanical (plant-based) medicines. He was the first naturopathic doctor to receive the "Orthomolecular Doctor of the Year" award in 2010. Dr. Prousky is the author of Hoffer & Prousky on Anxiety, Anxiety: Orthomolecular Diagnosis and Treatment, Naturopathic Nutrition, Principles & Practices of Naturopathic Clinical Nutrition, and The Vitamin Cure for Chronic Fatigue Syndrome.