Non-Cochrane · intervention · PM41487531
Efficacy of sublingual and oral vitamin B12 versus intramuscular administration: insights from a systematic review and meta-analysis.
Mazur Marta, Ndokaj Artnora, Salerno Claudia, et al. · Frontiers in pharmacology · 2025 · PubMed · doi:10.3389/fphar.2025.1602976
Findings
Population People of any age with vitamin B12 deficiency (or at risk)
16 findings
| Vitamin B12 supplementation by any route (oral, sublingual or intramuscular) | Baseline (pre-treatment) level; within-arm mean change, no between-route comparator | Serum cobalamin (vitamin B12) level Post-treatment versus baseline (follow-up varied by study) · Daily dose: 500-750 ug | MD 194 [93, 294] GRADE not reported 1 study |
| Vitamin B12 supplementation by any route (oral, sublingual or intramuscular) | Baseline (pre-treatment) level; within-arm mean change, no between-route comparator | Serum cobalamin (vitamin B12) level Post-treatment versus baseline (follow-up varied by study) · Daily dose: 2000-5000 ug | MD 462 [188, 736] GRADE not reported 3 studies |
| Vitamin B12 supplementation by any route (oral, sublingual or intramuscular) | Baseline (pre-treatment) level; within-arm mean change, no between-route comparator | Serum cobalamin (vitamin B12) level Post-treatment versus baseline (follow-up varied by study) · Daily dose: 1000-1500 ug | MD 424 [286, 563] GRADE not reported 14 studies |
| Vitamin B12 supplementation by any route (oral, sublingual or intramuscular) | Baseline (pre-treatment) level; within-arm mean change, no between-route comparator | Serum cobalamin (vitamin B12) level Post-treatment versus baseline (follow-up varied by study) · Underlying pathology: vitamin B12 deficiency (unspecified etiology) | MD 493 [306, 681] GRADE not reported 9 studies |
| Vitamin B12 supplementation by any route (oral, sublingual or intramuscular) | Baseline (pre-treatment) level; within-arm mean change, no between-route comparator | Serum homocysteine level Post-treatment versus baseline (follow-up varied by study) | MD -4.83 [-6.55, -3.11] Low Downgraded: risk of bias, imprecision, inconsistency 5 studies |
| Vitamin B12 supplementation by any route (oral, sublingual or intramuscular) | Baseline (pre-treatment) level; within-arm mean change, no between-route comparator | Serum cobalamin (vitamin B12) level Post-treatment versus baseline (follow-up varied by study) | MD 402.6 [293.6, 511.5] Moderate Downgraded: risk of bias, imprecision, inconsistency 15 studies |
| Vitamin B12 supplementation by any route (oral, sublingual or intramuscular) | Baseline (pre-treatment) level; within-arm mean change, no between-route comparator | Serum cobalamin (vitamin B12) level Post-treatment versus baseline (follow-up varied by study) · Age group: children (0-15 years) | MD 385 [297, 472] GRADE not reported 4 studies |
| Vitamin B12 supplementation by any route (oral, sublingual or intramuscular) | Baseline (pre-treatment) level; within-arm mean change, no between-route comparator | Serum cobalamin (vitamin B12) level Post-treatment versus baseline (follow-up varied by study) · Underlying pathology: other diseases | MD 148 [108, 187] GRADE not reported 2 studies |
| Vitamin B12 supplementation by any route (oral, sublingual or intramuscular) | Baseline (pre-treatment) level; within-arm mean change, no between-route comparator | Serum cobalamin (vitamin B12) level Post-treatment versus baseline (follow-up varied by study) · Age group: adults | MD 416 [263, 570] GRADE not reported 12 studies |
| Vitamin B12 supplementation by any route (oral, sublingual or intramuscular) | Baseline (pre-treatment) level; within-arm mean change, no between-route comparator | Serum cobalamin (vitamin B12) level Post-treatment versus baseline (follow-up varied by study) · Underlying pathology: gastrectomy | MD 365 [240, 489] GRADE not reported 4 studies |
| Oral vitamin B12 | Baseline (pre-treatment) level; within-arm mean change, no between-route comparator | Serum cobalamin (vitamin B12) level Post-treatment versus baseline (follow-up varied by study) | MD 349 [201, 497] GRADE not reported 12 studies |
| Oral vitamin B12 | Baseline (pre-treatment) level; within-arm mean change, no between-route comparator | Serum homocysteine level Post-treatment versus baseline (follow-up varied by study) | MD -3.64 [-6.03, -1.25] GRADE not reported 5 studies |
| Sublingual vitamin B12 | Baseline (pre-treatment) level; within-arm mean change, no between-route comparator | Serum homocysteine level Post-treatment versus baseline (follow-up varied by study) | MD -4.98 [-6.12, -3.85] GRADE not reported 2 studies |
| Sublingual vitamin B12 | Baseline (pre-treatment) level; within-arm mean change, no between-route comparator | Serum cobalamin (vitamin B12) level Post-treatment versus baseline (follow-up varied by study) | MD 276 [205, 348] GRADE not reported 5 studies |
| Intramuscular (IM) vitamin B12 | Baseline (pre-treatment) level; within-arm mean change, no between-route comparator | Serum homocysteine level Post-treatment versus baseline (follow-up varied by study) | MD -11.67 [-24.73, 1.40] GRADE not reported 3 studies |
| Intramuscular (IM) vitamin B12 | Baseline (pre-treatment) level; within-arm mean change, no between-route comparator | Serum cobalamin (vitamin B12) level Post-treatment versus baseline (follow-up varied by study) | MD 507 [290, 723] GRADE not reported 14 studies |
Included primary studies 48
Open in Studies| Study | Year | Also included by | Outcomes it informs here | Trial data |
|---|---|---|---|---|
| Adachi 2000 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Adachi 2000 Enteral vitamin B12 supplements reverse postgastrectomy B12 deficiency. PMID:10903597 | 2000 | this review only | not stated | not extracted yet |
| Altay 1999 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Altay 1999 Vitamin B12 absorption test and oral treatment in 14 children with selective vitamin B12 malabsorption. PMID:10100276 | 1999 | this review only | not stated | not extracted yet |
| Arican 2020 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Arican 2020 Various Neurological Symptoms with Vitamin B12 Deficiency and Posttreatment Evaluation. PMID:33936299 | 2020 | this review only | not stated | not extracted yet |
| Bensky 2019 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Bensky 2019 Comparison of sublingual vs. intramuscular administration of vitamin B12 for the treatment of patients with vitamin B12 deficiency. PMID:30632091 | 2019 | this review only | not stated | not extracted yet |
| Bolaman 2003 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Bolaman 2003 Oral versus intramuscular cobalamin treatment in megaloblastic anemia: a single-center, prospective, randomized, open-label study. PMID:14749150 | 2003 | this review only | not stated | not extracted yet |
| Castelli 2011 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Castelli 2011 Comparing the efficacy and tolerability of a new daily oral vitamin B12 formulation and intermittent intramuscular vitamin B12 in… PMID:21600388 | 2011 | this review only | not stated | not extracted yet |
| Kim 2011 Oral vitamin B12 replacement: an effective treatment for vitamin B12 deficiency after total gastrectomy in gastric cancer patients. PMID:21556950 | 2011 | this review only | not stated | not extracted yet |
| Korpeti 2023 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Korpeti 2023 Investigating the applicability of polar fabric phase sorptive extraction for the HPLC quantitation of salivary vitamin B12 following… PMID:36989615 | 2023 | this review only | not stated | not extracted yet |
| Kuzminski 1998 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Kuzminski 1998 Effective treatment of cobalamin deficiency with oral cobalamin. PMID:9694707 | 1998 | this review only | not stated | not extracted yet |
| Metaxas 2017 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Metaxas 2017 Early biomarker response and patient preferences to oral and intramuscular vitamin B12 substitution in primary care: a randomised… PMID:28421567 | 2017 | this review only | not stated | not extracted yet |
| Orhan Kilic 2021 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Orhan Kilic 2021 Sublingual methylcobalamin treatment is as effective as intramuscular and peroral cyanocobalamin in children age 0-3 years. PMID:34871525 | 2021 | this review only | not stated | not extracted yet |
| Parry-Strong 2016 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Parry-Strong 2016 Sublingual vitamin B12 compared to intramuscular injection in patients with type 2 diabetes treated with metformin: a randomised trial. PMID:27355231 | 2016 | this review only | not stated | not extracted yet |
| Ramos 2021 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Ramos 2021 Vitamin B12 supplementation orally and intramuscularly in people with obesity undergoing gastric bypass. PMID:33622624 | 2021 | this review only | not stated | not extracted yet |
| Roth 2004 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Roth 2004 Oral vitamin B12 therapy in vitamin B12 deficiency. PMID:14984828 | 2004 | this review only | not stated | not extracted yet |
| Sanz-Cuesta 2020 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Sanz-Cuesta 2020 Oral versus intramuscular administration of vitamin B12 for vitamin B12 deficiency in primary care: a pragmatic, randomised,… PMID:32819927 | 2020 | this review only | not stated | not extracted yet |
| Saraswathy 2012 Sa1100 Randomized Open Label Trial Comparing Efficacy of Oral Versus Intramuscular Vitamin B12 Supplementation for Treatment of Vitamin… DOI:10.1016/s0016-5085(12)60808-7 | 2012 | this review only | not stated | not extracted yet |
| Saraswathy 2012 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Schijns 2018 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Schijns 2018 Efficacy of oral compared with intramuscular vitamin B-12 supplementation after Roux-en-Y gastric bypass: a randomized controlled trial. PMID:29931179 | 2018 | this review only | not stated | not extracted yet |
| Sezer 2018 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Sezer 2018 Comparison of the efficacy of parenteral and oral treatment for nutritional vitamin B12 deficiency in children. PMID:29577819 | 2018 | this review only | not stated | not extracted yet |
| Sharabi 2003 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Sharabi 2003 Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route. PMID:14616423 | 2003 | this review only | not stated | not extracted yet |
| Tanaka 1981 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Tandon 2022 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Tandon 2022 Parenteral vs Oral Vitamin B12 in Children With Nutritional Macrocytic Anemia: A Randomized Controlled Trial. PMID:35642923 | 2022 | this review only | not stated | not extracted yet |
| Tillemans 2012 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Tillemans 2014 Effect of administration route on the pharmacokinetics of cobalamin in elderly patients: a randomized controlled trial. PMID:25031664 | 2014 | this review only | not stated | not extracted yet |
| Tugba-Kartal 2020 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Tugba-Kartal 2020 Comparison of Sublingual and Intramuscular Administration of Vitamin B12 for the Treatment of Vitamin B12 Deficiency in Children. PMID:33053572 | 2020 | this review only | not stated | not extracted yet |
| Yamane 1995 Clinical efficacy of intravenous plus oral mecobalamin in patients with peripheral neuropathy using vibration perception thresholds as an… DOI:10.1016/0011-393x(95)85135-6 | 1995 | this review only | not stated | not extracted yet |
| Yamane 1995 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Yazaki 2006 matched by author and year (probable) | NR | this review only | not stated | not extracted yet |
| Yazaki 2006 A single-center, double-blinded, randomized controlled study to evaluate the relative efficacy of sublingual and oral vitamin B-complex… PMID:17109579 | 2006 | this review only | not stated | not extracted yet |
Review question
| Element | Planned (methods) | Found (results) |
|---|---|---|
| Population | Subjects of any age diagnosed with vitamin B12 deficiency | People with vitamin B12 deficiency, adults and children (n=6,098 across 25 studies) |
| Intervention | Sublingual or oral administration of vitamin B12 | Oral, sublingual and intramuscular vitamin B12 (cyanocobalamin, methylcobalamin, hydroxocobalamin) |
| Comparison | Intramuscular administration of vitamin B12 | Pre-treatment baseline (mean change) and between-route comparison |
| Outcomes | Changes in serum vitamin B12 levels; clinical improvement of deficiency symptoms (homocysteine also extracted) | Serum cobalamin (15 studies in meta-analysis); serum homocysteine (5 studies, 10 comparisons) |
| Study designs | RCTs, non-randomized controlled trials, cohort studies, case-control studies | 13 RCTs, 2 case-control and 10 cohort studies (25 in qualitative synthesis; 16 in quantitative synthesis) |
| Timing | Not specified | Not specified |
AMSTAR 2 items
Two independent extractors rated each item. Their ratings are shown side by side because they have not been reconciled yet. The overall rating follows Shea et al. 2017: one critical flaw gives Low, more than one gives Critically Low.
| Item | Extractor A | Extractor B | Agree |
|---|---|---|---|
| 1Research question includes PICO components | Yes | Yes | yes |
| 2Protocol established before the reviewcritical | Partial Yes | Partial Yes | yes |
| 3Choice of study designs explained | Yes | Yes | yes |
| 4Comprehensive literature searchcritical | Partial Yes | Partial Yes | yes |
| 5Study selection in duplicate | Yes | Yes | yes |
| 6Data extraction in duplicate | Yes | Yes | yes |
| 7List of excluded studies with reasonscritical | No | No | yes |
| 8Included studies described in detail | Partial Yes | Partial Yes | yes |
| 9Risk of bias assessed satisfactorilycritical | RCT: Partial Yes · NRSI: Partial Yes | NRSI: Partial Yes · RCT: No | no |
| 10Funding of included studies reported | No | No | yes |
| 11Appropriate meta-analysis methodscritical | RCT: No · NRSI: No | NRSI: No · RCT: No | no |
| 12Impact of risk of bias on the pooled results | No | No | yes |
| 13Risk of bias accounted for in interpretationcritical | Yes | Yes | yes |
| 14Heterogeneity explained | Yes | Yes | yes |
| 15Publication bias investigatedcritical | Yes | Yes | yes |
| 16Conflicts of interest reported | Yes | Yes | yes |
| Overall | Critically Low | Critically Low | yes |