Reference Country Study design Follow‐up Funding	Original cohort (N total) Population sampled Exclusion criteria Study population	Ascertainment of outcome	Exposure groups Duration Exposure assessment method	Incident cases	Results
Anonymous (2009) Australia Case series NA NR	N = 2 Population: one woman with symptoms of neuropathy and one woman diagnosed with neuropathy Exclusion criteria: NA Lost to follow‐up (%): NA Sex (% of women): 100 Age (y): Case 1: 39 Case 2: 69	Reported to the Australian pharmacovigilance system	Vitamin B6 (mg/day) Case 1: 50 + multivitamins (may contain B6) Case 2: 600 Duration Case 1: daily intake for 3 month Case 2: daily intake for 3–4 years Type of vitamer: NR Method: Self‐report	NA	Symptoms experienced Case 1: Burning and electric shock sensations Case 2: Gait and clinical diagnosis of sensory neuropathy
Franzblau et al. (1996) USA CS NR NR	N = 125 Company 1: (n = 50), company 2: (n = 75) Population sampled: Workers from two companies (automotive parts manufacturer) Inclusion criteria: Company 1: all workers Company 2: only workers in selected jobs Lost to follow‐up (%): 0 n  = 125 Sex (% women): 67 Age (y): 36.6 ± 11.3	1. Self‐reported (questionnaire) of 9 symptoms at 15 body locations. CTS symptoms defined as: numbness, tingling, burning or pain in wrists, hands or fingers 2. Electrophysiologic testing: – Sensory nerve conduction studies (median and ulnar sensory nerve) – Mid‐palm temperature tests CTS definition: Reported symptoms potentially consistent with CTS and evidence of median mononeuropathy (MM) in the same hand.	PLP (n = 112), nmol/L: 128.0 ± 81.1 (23.6–379.6) Deficiency: < 30 nmol/L Method: radioenzymatic assay	Cases, n Dominant hand CTS symptoms: 34 No CTS symptoms: 78 MM: 20, 17.6% No MM: 92 CTS: 10 No CTS: 102 Non‐dominant hand CTS symptoms: 27 No CTS symptoms: 85 MM: 15, 13.6% No MM: 97 CTS: 5 No CTS: 107 Either hand CTS symptoms: 39 No CTS symptoms: 73 MM: 29, 24.8% No MM: 83 CTS: 14 No CTS: 98	PLP concentration (nmol/L) Dominant hand CTS symptoms: 130.7 ± 93.3 No CTS symptoms: 126.8 ± 75.8 p > 0.25 MM: 145.4 ± 104.3 No MM: 124.2 ± 75.3 p > 0.25 CTS: 145.0 ± 122.8 No CTS: 126.3 ± 76.5 p > 0.25 Non‐dominant hand CTS symptoms: 133.9 ± 95.6 No CTS symptoms: 126.1 ± 76.5 p > 0.25 MM: 111.0 ± 75.8 No MM: 130.6 ± 82.0 p > 0.25 CTS: 117.6 ± 75.5 No CTS: 128.5 ± 81.7 p > 0.25 Either hand CTS symptoms: 133.3 ± 90.9 No CTS symptoms: 125.1 ± 75.9 p > 0.25 MM: 1.06 ± 0.17 No MM: 127.1 ± 76.6 p > 0.25 CTS: 138.4 ± 110.8 No CTS: 126.5 ± 76.6 p > 0.25
Keniston et al. (1997) USA CS NR NR	N = 441 Population sampled: Volunteer male and female workers from six industries, workers at university, homemakers employed in various occupations and from an exercise study at university Exclusion criteria: None Lost to follow up (%): 0 n = 441 Sex (% women): 39 Age (y): 44.5 ± 9.3 (19–71)	Self‐reported presence, frequency, and nature of hand and wrists symptoms (via interview), including: – Numbness, tingling or nocturnal awakening (defined as specific CTS symptoms) – Pain, tightness and clumsiness (defined as non‐specific CTS symptoms, not relevant if isolated presence) Nerve conduction studies of the median nerve CTS definition: Minimum 1 specific symptom and confirmed by a positive median nerve slowing. Cut‐off at 100 nmol/L plasma PLP, at which level vitamin B6 intake is associated with 3.5 mg/d (supplementation ~ > 2 mg/d)	Self‐reported vitamin B6 supplementation (mg/day): All: 0–200 Women, median: 1 Men, median: 0 G1 (n = 87): no symptoms or slowing (control) G2 (n = 56): symptoms only G3 (n = 115): slowing only G4 (n = 183): CTS (slowing and symptoms) Plasma PLP, nmol/L (n = 441): mean ± SD, median G1: 63.2 ± 72.4, 45.9 G2: 64.8 ± 70.7, 39.6 G3: 62.3 ± 64.5, 44.6 G4: 67.4 ± 73.5, 43.5 Plasma PLP, nmol/L (n = 218), mean ± SD, median no vitamin supplements and plasma PLP ≤ 100 nmol/L) G1: 38.7 ± 16.5, 35.6 G2: 30.9 ± 15.6, 29.0 G3: 38.0 ± 18.2, 36.3 G4: 38.8 ± 19.1, 35.6	Plasma PLP > 100 nmol/L (n = 50): 20% (n = 10) were diagnosed with CTS, of which 80% (n = 8) took B6	Chi2 + F‐test: G1 (control) + G2 + G3 + G4: X 2   = 2.5, p = 0.476 + F = 0.144, p = 0.933 Stepwise multiple regression analysis*: Vitamin B6 supplementation independent predictor of: – Prevalence of definite CTS, p = 0.020 (supplemented and unsupplemented males and females) – Carpal tunnel release surgery, p = 0.040 (supplemented and unsupplemented males and females), p = 0.101 (all females) Plasma PLP independent predictor (in unsupplemented female) of: – Prevalence confirmed CTS, p = 0.020 (Significant correlation between PLP and frequency of tingling, [R = −0.18], p = 0.031) and frequency of awakening, [R = ‐0.23], p = 0.005) *Adjusted for age; gender; BMI; alkaline phosphatase; cigarette smoking
Shrim et al. (2006) Canada PC B6 intake: 9 ± 4.2 wks Total: ≈ 32 wks Unclear	N = 192 Population sampled: General population + health professionals Exclusion criteria: NR % lost to follow up: 0 n = 192 Sex (% women): 100 Age (y): G1: 32.5 ± 4.4 G2: 33.1 ± 4.2	Self‐report of adverse events, specifically during the period of B6 intake	Vitamin B6 intake via supplements (mg/d): G1 (n = 96): 132.3 ± 74 (> 5 0), duration: ≈ week 7–16 G2 (n = 96): 0 Type of vitamer: NR Method: NR	NR	No adverse effects Heterogeneity: Parity, p = 0.03, smoking status, p = 0.002
Blackburn and Warren (2017) NR Case report NA NR	N = 1 Population: A male with symptoms of peripheral neuropathy Exclusion criteria: NA Lost to follow up (%): NA Sex (% women): 0 Age (y): 65	– Self‐report of physical limitations – Testing of tendon reflexes and sensations to modalities – Pinprick and vibratory sensational testing Clinical examination (mentation, orientation, cranial nerves, motor strength and tone and balance (Romberg test))	Vitamin B6 intake: 6 energy drinks/d (content: 300% DRV/drink) Vitamin B6 intake, mg/d: 30.6 Vitamin B6 status (blood), ng/mL: 62.3 Duration: NR Type of vitamer: NR Method: Self‐report + blood sample	NA	– Decreased sensation to multiple modalities – Decreased pinprick in bilateral lower extremities – Absence of vibratory sensation in great toes, medial malleoli and hands bilaterally – Normal mentation, orientation, cranial nerves, motor strength and ton Romberg test (balance test): positive Vitamin B6 cessation improved neuropathy symptoms
Falcone and Sowa (2013) USA Case series NA NR	N = 5 Population: Patients with neuropathy symptoms reporting to clinic asked to replace B6 supplementation with P5P Exclusion criteria: NA Lost to follow up (%): NA Sex (% women): 80 Age (y): 39–81	Self‐reported neuropathic pain in distal limbs Electrodiagnostic measurements: Large fibre polyneuropathy n = 2 Chronic right L4‐5 radiculopathy: n = 1	Serum pyridoxine, ng/mL: 53.4–148.5 Normative range, ng/mL: 2.1–21.7 Method: Blood sample	NA	Improved neuropathic pain
Dalton and Dalton (1987) UK Study 1: CC Study 2: case‐report Follow‐up (Study 1): 6 months after B6‐discontinuation NR	Study 1: N = 172 Study 2: N = 1 Population sampled: Study 1: women with premenstrual syndrome Study 2: woman with neurological symptoms Exclusion criteria: Study 1: NR Study 2: NA % lost to follow‐up: 0 Sex (% women): 100 Age (y): Study 1 Cases: 41.5 ± 8.8 Controls: 41.9 ± 9.8 Study 2: 49	Study 1: Self‐report of altered sensations in limbs or skin and notice of muscle weakness or pains Study 2: Self‐reported measures: – Complains of paraesthesia of hands at night, – Electric shock pains – Numbness of fingertips – Itching between shoulder blades – Hypersensitivity to stoking with cotton wool on her back and lower limbs Reflexes and muscle power normal Lhermitte's test negative	Vitamin B6 intake, mg/d Study 1: Cases: 117 ± 92 Controls: 116 ± 66 Study 2: 75 Duration (y): Study 1 Cases (neurotoxic): 2.9 ± 1.9 Controls: 1.6 ± 2.1 p < 0.01 Study 2: 2 Serum vit B6 Study 1, %  > 34 ng/mL Cases: 70 Controls: 55 *34 ng/mL = upper limit of testing Study 2, ng/mL: > 34 Normative range: 3.6–18 ng/mL Method: Self‐report and blood sample	Study 1: % with neurological symptoms (serum B6 > 18 ng/mL) Cases < 50: 20 < 100: 38 < 200: 31 < 500: 11 Controls < 50: 32 < 100: 38 < 200: 14 < 500: 16 Cases (neurological symptoms in serum B6 > 18 ng/mL, n = 103) Paraesthesia: 59 Bone pains: 45 Hyperesthesia: 33 Muscle weakness: 33 Numbness: 21 Fasciculation: 18 Study 2: NA	Study 1: After 2 months of B6‐discontinuation: B6 levels within the normal range except for 11 women (controls: 4), whose levels were below normal (3.6 ng/mL) After 3 months: 55% reported partial or complete recovery of neurological symptoms After 6 months of B6‐discontinuation: all reported complete recovery of neurological symptoms Cases (n = 7) who did not stop B6 intake: Continuation of neurological symptoms + B6 level remained elevated until discontinuation of B6 Study 2: B6 discontinuation eased symptoms within 3 months Return with neurological symptoms: B6 levels were > 34 ng/mL after restarting with B6 supplements
Visser et al. (2014) Netherlands CC NR Supported by grant (WAR 07–24) from the Prinses Beatrix Fonds	N = 577 Population sampled: G1: patients with chronic idiopathic axonal polyneuropathy (CIAP*) G2: healthy controls *CIAP defined as predominantly sensory polyneuropathy without ataxia, predominantly sensory polyneuropathy with ataxia or sensorimotor polyneuropathy Exclusion criteria: Vit B6 supplementation unknown; vit B6 supplementation after debut of polyneuropathy symptoms; pure small fibre neuropathy or typical sensory ataxic polyneuropathy. % Lost to follow up/excluded: 13 n = 521 G1: 381 G2: 140 Sex (% women): G1: 30 G2: 38 Age (y, mean): G1: 64.7 G2: 64.0	– All patients clinically evaluated for polyneuropathy in a standardised fashion – Severity of the polyneuropathy graded by calculation and summation of sensory and motor sum scores of the lower limbs – Manual muscle strength testing performed of tibialis anterior, gastrocnemius, peroneal, and toe extensor muscles, and graded according to the Medical Research Council (MRC) scale resulting in a motor sum score from 0 to 40 for both lower limbs.	Whole blood PLP (nmol/L, median (range)): Non‐users of B6 supplements G1: 90 (38–255) G2: 94 (41–826) Users of B6 supplements G1: 135 (43–2,967) G2: 165 (94–2,373) Vit B6 supplements, mg/d (median, range): G1 (n = 112): 2.1 (0.5–200) G2 (n = 29): 2.8 (0.4–71) Duration (median (range) y): 7.4 (0.5–81) Type of vitamer: Blood: PLP (normative range: 26–102 nmol/L) Supplements: NR Method: Blood: Reversed‐phase fluorescence detection Use of supplements: Questionnaire	CIAP, n G1: 381 G2: 0 Predominantly sensory polyneuropathy without ataxia, n G1: 245 G2: 0 Predominantly sensory polyneuropathy with ataxia, n G1: 33 G2: 0 Sensorimotor polyneuropathy, n G1: 103 G2: 0	CIAP not significantly (NS) associated with elevated vitamin B6 levels Note : More patients (31%) than controls (22%) used B6 supplements, (OR 1.7 (95% CI 1.0–2.7) p = 0.032) Vitamin B6 levels NS different between patients and controls, p = 0.58* Follow‐up of patients confirming cessation of vitamin B6 supplement‐use showed slow progression of symptoms in 64%, stabilisation in 26%, and regression in 10%. ‘An association between CIAP and vitamin B6 exposure or elevated vitamin B6 levels appears unlikely’ *Initially adjusted for gender and age Further adjusted for smoking and alcohol use (did not change overall conclusions)
Baer (1984) USA Case report NA NR	N = 1 Population: A woman with cutaneous skin changes and neuropathy Lost to follow‐up: NA Sex (% women): 100 Age (y): 36	History and clinical manifestations, neurologic and general physical examination and routine laboratory tests	Pyridoxine: 4 g/day Duration: 4 years (discontinuation of intake after she had informed the dermatologist about her intake) Method: Self‐reported	NA	Symptoms: Developing numbness of the feet and tips of the fingers Discontinuation of pyridoxine for 3 months did not improve the neurologic manifestations
Scott et al. (2008) USA Case series Patients (n = 14): Follow‐up phone calls after 6 months of B6 discontinuation NR	N = 26 Population: Patients with elevated vit B6 levels and neuropathic symptoms Exclusion criteria: Patients with hereditary neuropathy and laboratory abnormalities of any kind (besides elevated B6 levels) that could explain their symptoms Lost to follow‐up (%): NA Sex (% women): 35 Age (y, mean): At presentation: 57.6 (28–84) At onset of symptoms: 53.8 (27–76)	Quantitative sensory testing (QST) Electromyography (EMG) Nerve conduction studies (NCS)	Patients with daily use of specific vit B6 supplements or B‐complex vitamins + daily multivitamins, n (%): 14 (53.8) Reported B6 dose (mg/d) Patient 1 + 2: 53 Other patients: NR Duration (y): Patients 1 + 2: 34 Other patients (23/26): > 1 Blood pyridoxine level (ng/mL, mean (range)): 68.8 (23.3–177.3) Normal level 3–20 Method: Self‐reports + blood sample	NA	QST (n = 10): Abnormal, n (%): 8 (80) EMG/NCS findings (n = 26), n (%): Normal: 17 (65) Mild sensorimotor axonal neuropathy: 7 (27) Mild sensory axonal neuropathy: 1 (4) Moderate sensorimotor axonal neuropathy: 1 (4) Self‐reported symptoms, %: Numbness: 96 Burning pain: 50 Tingling: 58 Balance difficulties: 31 Weakness: 8 Progressive involvement of distal extremities (legs worse than arms): 100 Lower extremities involvement: 35 Upper and lower extremities involvement: 62 Only upper limb involvement: 1 Deficits in facial sensation and taste: 1 No patient had strictly motor symptoms Neurological examinations, %: Decreased pinprick: 39 Decreased vibration: 42 Deficits in proprioception and/or light touch: 19 Gait dysfunction: 12 Decreased deep‐tendon reflex abnormalities: 12 Weakness and muscle atrophy: 8
Chaudary et al. (2003) UK RC 3–42 mo (this is performed before inclusion into the study, c.f. the retrospective design) NR	N = 584 Population sampled: Men and women attending a nutritional therapy practice for help with various complaints and prescribed >30 mg/day vitamin B6 supplements for more than 3 months. Lost to follow‐up (%): 0 n = 555 Sex (% women): NR Age (y): 14–76	Self‐reported on the Nutrition Programme Questionnaire that reported predefined symptoms: Tingling hands, insomnia (night restlessness), acne, and skin rashes The questionnaire by the nutritional therapist was done before and after vitamin B6 supplementation (≥ 30 mg/day)	Vitamin B6 from supplements (mg/day): 30–230 (Individual mean dose calculated from start dose to end dose) Duration: At least 3 months supplementation before entry into the study Background intake: NA Type of vitamer (%): Pyridoxine: 93.3 PLP: 6.3 PN‐HCl: 0.4	NA	Symptoms (tingling hands, insomnia, rash, acne) reduced in frequency after 3–42 months of vitamin B6 supplementation over the full dose range (p < 0.001) ‘On analysis the majority of the participants in both the ‘no change in tingling hands’ group and ‘improvements in tingling hands’ group had complained about fatigue… [and other symptoms of vitamin B6 deficiency]’. 114 participants attended the nutrition therapy clinic with no reported symptoms, 91 did not develop symptoms associated with toxicity and 23 experienced symptoms after vitamin B6 supplementation (majority with 101–150 mg/day).
Vrolijk et al. (2020) Netherlands Case series NA The Netherlands Pharmacovigilance Centre Lareb and Natuuren Gezondheidsproducten Nederland (NPN)	N = 173 Population sampled: Cases of vitamin B6‐induced neuropathies from 1991 to 2020 (see under ‘comments’ to this paper) reported to the Netherland Pharmacovigilance Centre Lareb Lost to follow‐up (%): NA Sex (% women): NR Age (y): 54 ± 15	Self‐reports by the cases, other methods NR (no quality check of supplements as reported by patients, and no check of adherence to the advised daily doses)	Vitamin B6, mg/d (intake from supplements (PLP, PN)): 0.5–250 36.7 ± 24.4 96 out of 173 used vitamin B6 supplementation without co‐medication Plasma PLP, nmol/L (n = 70): 1078 ± 1124 (88–5656) Duration: NR Type of vitamer: Supplements: Pyridoxal 5′ phosphate (PLP) and pyridoxine (PN) Blood: Plasma PLP Method: Self‐reported	Complaints reported: Cases using vitamin B6 supplements < 21 mg/day: 39% (67/173 cases) neurological complaints Cases using vitamin B6 supplements > 21 mg/day: 45% (78/173 cases) complaints (no information about dose in 16% [28 cases])	PLP: 3.5% of reported cases PN: 96.5% of reported cases Pearson correlation analysis: NS correlation between the dose of PN and plasma level of PLP, r = 0.15
Chaudary and Cornblath (2013) USA Case series NA NR	N total = 78 Population sampled: Patients with neuropathy and B6 levels < 26 ng/mL Exclusion criteria: Patients with well‐recognised causes of neuropathy (diabetes, chemotherapy, CIPD, alcohol, CMT, and multiple myeloma) Lost to follow‐up (%): 35 n = 51 Sex (% of women): 47 Age (y, median): 58	Sensory symptoms: Small fibre sensory symptoms Large fibre sensory symptoms Loss of modality Reflexes Weakness Normal sensory nerve action potential (SNAP) amplitudes CAMP Skin biopsy, intraepidermal nerve fibre density (IENFD)	Blood pyridoxine levels (ng/mL mean (range)): 114 (31–348) Elevated levels: >26 ng/mL Duration: NR Method: Blood samples		N, with symptoms Small fibre sensory symptoms: 46 Large fibre sensory symptoms: 15 Small fibre modality loss: 26 Large fibre modality loss: 17 Reduced reflexes:15 Mild distal weakness: 6 Reduced SNAP amplitudes: 9 Reduced CAMP: 4 Reduced skin biopsy, IEFND: 18 Mean pyridoxine level did not correlate with neuropathy severity Very high dose pyridoxine (NR) associated with a predominantly sensory, small fibre > large fibre, length‐dependent or independent neuropathy
Berger et al. (1984) USA Case report NA NR	N = 1 Population: one woman (general) Lost to follow‐up (%): NA Sex (% women): 100 Age (y): 34	Self‐reported symptoms Clinical examination at the hospital	Vit B6 intake (mg/d): First two years: 200 Third year: 500 Once per week in the last year: 800 Duration: 200 mg/day for two years, increased to 500 mg/day for one year Type of vitamer: NR Method: Self‐reported	NA	Signs of peripheral neuropathy Signs decreased 3 wks after vit B6 supplementation cessation and continued to decrease in following months Self‐reported: – Electric shocks down the spine – Progressive gait unsteadiness – worse when walking and in darkness – Numbness and paresthesias of both feet – Numbness of both hands, lips and left cheek Clinical examination: – Marked sensory ataxia – Absent tendon reflexes and flexor plantar responses – Needed assistance to walk – Somatosensory evoked potential showed prolonged latency between lumbar and cervical sites
Foca (1985) USA Case report NA NR	N = 1 Population: Woman with difficulty walking and frequent falling. History of bilateral carpal tunnel syndrome (CTS) Lost to follow‐up (%): 0 Sex (% women): 100 Age (y): 81	Clinical examination*: Test of voluntary movement Reflexes Pinprick Position and vibratory sense * at 3 wks post cessation of vit B6 intake	Pyridoxine intake (g/d): 4.5 Blood vit B6 (ng/mL): 9 At time of admission medications: Dyazide (triamterene hydrochlorothiazide), vit A, C, D, and B complex vitamins Duration: Gradually increasing vit B6 for several months, 4.5 g/d for the last three wks Normative range: Blood: 3.6–18 ng/mL Intake: 2–4 mg/d Method: Self‐reported + blood samples	NA	Clinical examination – Sensation to pin in lower extremities (more distally and more in the right lower extremity) – Position sense was absent in both lower extremities – Vibratory sense was absent in toes and reduced up to the knees bilaterally – Ambulation reduced with ataxia and poor foot placement – Depressed reflexes bilaterally Electrodiagnostic testing: Slowing motor conduction in both peroneal and tibial nerves; sensory latency was unobtainable in right slow in left sural nerve
Brush et al. (1988) UK RC NA NR	N = 630 Population sampled: General population, women attending the PMS Clinic Inclusion criteria: PMS Exclusion criteria: Menstrual distress. Intermittent conditions liable to occur at any stages of the cycle Lost to follow‐up (%): 0 n = 630 Sex (% women): 100 Age (y % patients at 1st visit): < 14: 0.2 15–25: 10 26–35: 46.2 36–45: 40.2 > 45: 3.3	Clinical diagnosis of peripheral neuropathy Definition of PMS: Occurring in the second half of the menstrual cycle and finishing within 24–48 h of the onset of menstruation. Most common symptoms: mood changes, fluid retention and/or redistribution, breast discomfort and tension headache	Pyridoxine hydrochloride supplement (mg/d) initially at 40–100, followed by 120–200 Duration and % patients < 6 mo: 45.9 6–12 mo: 34.6 1–2 y: 12.6 3–4 y: 4.6 4–5 y: 2.3 Normative range: NR Method: NR	% response to treatment recorded as good (no significant residual complains) of patients taking 100–150 mg/d pyridoxine: 40 % response to treatment recorded as good of patients taking 160–200 mg/d pyridoxine: 60	No symptoms consistent with a diagnosis of peripheral neuropathy reported
Schaumburg et al. (1982) USA Case report NA NR	N = 2 Population: A man and woman with sensory neuropathy symptoms Exclusion criteria: NA Lost follow‐up (%): NA Sex (% women): 50 Age (y): Man: 25 Woman: 37	Neurological examinations (pinprick test, sensory test of temperature, touch and vibration, test of distal tendon reflexes)	Pyridoxine supplement (mg/d): Man: 3000 Woman: 2000 RDI: 2.5 Duration (mo): Man: 3 Woman: 11 Method: Self‐report	NA	Sensory neuropathy measures (n = 2): – Numbness in feet and hands – No dysesthesias, facial involvement or weakness – Moderately diminished sensation to pinprick, temperature, and touch sensation – Severe loss of vibration sense – Distal tendon reflexes absent – Normal strength – Electromyograms normal – Motor nerve conduction normal Discontinuation of pyridoxine after 1 y: No improvements in sensory neuropathy
Waterston and Gilligan (1987) Australia Case report NA NR	N = 1 Population: one woman Lost to follow‐up (%): NA Sex (% women): 100 Age (y): 20	Self‐reported (3‐mo recall) symptoms and examined in the hospital Physical examination power and coordination, Knee‐ and ankle‐jerks. Gait. Romberg's test Sensory examination (proprioception, vibration and temperature sensation, light touch sensation)	Pyridoxine supplementation (mg/d): 1000 (Average daily requirement ≈ 1.5 mg/d with 100 g of protein) Duration: 12 months Method: Self‐reported	NA	Self‐reported symptoms: – Increased numbness and paraesthesia in both feet – Aching legs – Balance deteriorated, especially poor in darkness Physical examination: – Impaired proprioception, vibration, and temperature sensation – Positive for Romberg's sign – Slowing in sensory fibres in lower and upper limbs – Prolonged distal motor latency Symptoms worsened 3 wks later – moved to upper limbs Symptoms slowly decreased after 4 months of vitamin B6 supplementation termination
Dalton et al. (1985) UK Case series 2 months after vit B6 discontinuation NR	N = 58 Population: Women taking pyridoxine for premenstrual syndrome Exclusion criteria: NA Lost to follow‐up (%): 53 n = 58 Sex (% women) 100 Age (y): 42 ± 9	Sensory neuropathy Burning, shooting, tingling pains Paraesthesia of limbs Clumsiness Ataxia Perioral numbness	Vitamin B6 supplementation (mg/d): 50–300 Normative range Intake : 2–4 mg/d Blood: 3–18 ng/mL Method: Self‐reported	Symptoms of sensory neuropathy, n per patient (B6 serum levels > 18 ng/mlL: At first visit (n = 58): 3.4 2 months after termination of B6: (n = 27): 1.04	Improvement in neuropathy symptoms 2 months after vitamin B6 discontinuation: p < 0.001
Bacharach et al. (2017) USA Case report 1 y after initial presentation NR	N = 1 Population: One woman with progressive burning, numbness, tingling, and weakness in all 4 extremities for 2 years Lost to follow‐up (%): NA Sex (% women): 100 Age (y): 41	1. Physical examinations (touch, vibration, proprioception temperature, pinprick, gait test, Romberg test) 2. Electromyography/ nerve conduction study 3. Quantitative sudomotor axon reflex test (QSART)	Intake: NR Duration: NR (symptoms >2 y) Initial pyridoxic acid (PA) concentration, μg/L: 463 (B‐vitamin complex, dose NA) *Normative range: 3–30 μg/L PA 4 mo after restriction of vit B6 (food and supplements)*, μg/L: 2440 PA 4 mo after restriction of energy drinks high in vit B6, μg/L: 760 *accidentally consumed energy drinks high in vit B6 Method: Blood sample	NA	1. Symptoms consistent with small fibre neuropathy 2. Nerve conduction study (left arm and leg): Moderate chronic sensory polyneuropathy + left‐sided, mild median mononeuropathy across the wrist 3. QSART: Abnormal postganglionic sympathetic sudomotor responses at the proximal/distal leg and foot sites Follow‐up 1 y after initial presentation: no significant improvement in symptoms
Vasile et al. (1984) USA Case report 3 mo after cessation of vit B6 NR	N = 1 Population: A woman experiencing difficulty with ambulation over a 4‐month period. Known with mild osteoarthritis (non‐medicated), no history of syphilis, alcohol abuse, or degenerative disorder. Took vitamin B6 supplementation for carpal tunnel syndrome, as ordered by her physician. Lost to follow‐up (%): 0 Sex (% women): 100 Age (y): 58	Physical examination and electrodiagnostic tests (sensory conduction studies, electromyography, nerve biopsy)	Pyridoxine intake (mg/d): 3000 Duration (mo): 6 Method: NR	NA	Physical examination: – Abnormal gait compatible with sensory neuropathy – Absent vibration and proprioceptive modalities in the distal lower extremities, and reduced awareness in the upper extremities – Lhermitte's sign – Muscle testing normal in all extremities – Achilles jerk reflexes absent bilaterally – Biceps and patellar reflexes diminished bilaterally Electrodiagnostic tests: – Normal motor conduction velocities and terminal latencies in all extremities (but CTS present) – Evoked response to sural nerve testing – Electromyography negative for acute or chronic denervation – Chronic active axonal neuropathy found in sural nerve biopsy Progression of symptoms while on vitamin B6 treatment: awareness to pinprick stimulation in a glove and stocking distribution, and gait abnormality 3 months after cessation of vit B6: Improved gait pattern and sensory awareness. Lhermitte's sign absent, normal sensory conduction velocity in upper extremities. Sural nerve response still present.
Malek et al. (2020) Lebanon Case report 1st: 1 mo 2nd: 18 mo NR	N = 1 Population: A non‐smoking man working as an energy consultant with no history of exposure to hazardous substances, no history of alcohol use or abuse. Treated for depression with escitalopram. Progressive numbness and imbalance for 12 years. Lost to follow‐up (%): NA Sex (% women): 0 Age (y): 54	Self‐reported (10 y post onset of symptoms) and clinical examination Physical examination Gait, Romberg's test, reflexes Sensory examination (vibration sense) Electrophysiological examination Electromyography (EMG) Somatosensory‐evoked potentials (SSEP)	Vitamin B6 intake from self‐prescribed medication containing pyridoxine (mg/d): 30* *also consumed energy drinks with high amounts of vitamin B6 (exact amount NR) Vit B6 level at 1st visit (ng/mL): 60.2 (reference 3.6–18) Vit B6 level at follow‐up after cessation of medication and energy drinks (ng/mL): 20.9 (reference 5–30) Duration (y): ~ > 9 Type of vitamer (blood): NR Normative range: 3.6–18 ng/mL Methods: Self‐reported and blood sample	NA	Symptoms at first visit: Self‐reported: Gait instability Near falls Medical examination: Positive Romberg's test Decreased vibratory sense distally Absent deep tendon reflexes Electrophysiological examination: Severe, generalised, and non‐length dependent sensory neuronopathy/ganglionopathy EMG and SSEP absent sensory responses in bilateral sural, median and ulnar nerves Abnormal tibial SSEP responses 1st Follow‐up: Pyridoxine‐induced diffuse sensory ganglionopathy 2nd Follow‐up: Pyridoxine‐induced diffuse sensory ganglionopathy remained stable
Schaumburg et al. (1983) and Anonymous (1984) (S6) USA Case series & Case report 7 mo after pyridoxine withdrawal NR	N = 7 Population: General population with symptoms of peripheral neuropathy Subject 1 (S1): Case with ‘typical clinical presentation’ exemplifying other cases Subject 2–7 (S2‐S7): Other cases Lost to follow‐up (%): NA Sex (% women): 71 Age (y): 20–43	Self‐reported and clinical examined S1 reported in more detail S2‐6 reported together S6 reported in separate publication Examination: Sensory profile Sural‐nerve biopsy Sensory‐, motor, tibial‐ and median‐nerve conduction Somatosensory response S1 and S6: Physical examination: Walking gait Reflexes Babinski test Sensory examination: Touch, temperature, pinprick, vibration, joint position Electrophysiologic examination: Motor nerve, sensory‐nerve, needle, electromyography, somatosensory response, tibial‐nerve, median‐nerve	Pyridoxine intake (g/d) S6: – 2 y before seeking medical attention: 0.5 – 1 y before seeking medical attention: 5 S1‐7: 2–6 (max daily dose; Only S2 and S5 started out with high doses, the other cases started with 0.5–1 g/day and increased the intake steadily. None experienced any symptoms at doses < 2 g/day Duration: 2–40 months Pyridoxine in blood (ng/mL): S7: >30 Normative range: 3.6–18 Method: Self‐reported and blood samples		S1: – Lhermitte's sign (tingling sensation down the neck into feet and toes when flexing neck) – Walk with cane only – Gait broad‐based and stamping – Unable to walk with eyes closed – Marked pseudoarthrosis of outstretched arms – Limb reflexes and Babinski signs absent – No sensory‐ nerve action potentials – Motor‐nerve conduction and electromyogram normal – Somatosensory evoked response studies: Unilateral tibial nerve stimulation, no response – Bilateral tibial nerve stimulation: No response over the lumbar or cervical spine but a cerebral response of very low amplitude was noted S2‐7: – Sensory loss in extremities – Sensations of touch, temperature, pinprick, vibration and joint position severely impaired in the upper and lower limbs – Sural nerve biopsy (non‐specific axonal degeneration), n = 2 – Somatosensory evoked responses, n = 2 – Distal sensory‐nerve conduction: Absent in all nerves, n = 4 – Mild subjective alteration of touch‐pressure and pinprick sensation over the cheeks and lips, n = 6 – Sensory‐nerve action potentials not be elicited unilateral tibial nerve and bilateral tibial nerve stimulation produced no response, n = 6 S6: Self–reported symptoms: – Difficulty walking especially in darkness – Difficulty handling small objects – Changes in feeling in lips and tongue – Lhermitte's sign Clinical examination findings: – Walk with cane only and unable to walk with closed eyes – Gait broad–based and stamping – Marked pseudoathetosis of the outstretched arms – Limb reflexes and Babinski signs absent – Sensations of touch, temperature, pinprick, vibration and joint position were severely impaired in upper and lower limbs After stopping pyridoxine supplementation symptoms decreased in all cases 7 months after pyridoxine withdrawal: – Sensory nerve responses were absent – Motor nerve conduction normal – Somatosensory evoked responses definite improvement in central conduction and mild improvement in peripheral conduction
Parry and Bredesen (1985) USA Case series 3–18 months after vit B6 supplementation stopped NR	N = 16 Population: Women with symptoms of peripheral neuropathy, one patient with inherited neuropathy Lost to follow up (%): 31 Sex (% women): 100 Age (y): 25–53	Clinical examination 8 patients at clinic and 8 by telephone interview Electrophysiologic studies (n = 7) Sural nerve biopsy (n = 2) Follow‐up evaluations, n: By telephone: 8 At examination: 5	Pyridoxine supplementation (mg/d): 200–5000 Duration (mo): 1–72 Normative range: NR Method: Self‐reported	NA	Symptoms (n = 16), % of patients Numbness: 100 Paresthesia: 100 Ataxia: 81 Lhermitte's sign: 50 Pain: 31 Weakness: 6 Signs (n = 8), % of patients Sensory deficit: 100 Sensory ataxia: 88 Romberg's sign: 88 Loss of Achilles reflexes: 100 Loss of other deep tendon reflexes: 0 Weakness: 13 Electrophysiologic studies, n: Needle EMG normal: 7 Sensory nerve conduction velocity slowed mild: 7 Sensory nerve action potential absent or severely reduced amplitude: 7 Compound muscle action potential amplitudes and motor nerve conduction velocity normal: 7 Sural nerve biopsy (n = 2): myelinated fibre density moderately reduced, myelin debris indicated axonal degeneration, no segmental demyelination or myelinated fibre regeneration
Gdynia et al. (2008) Germany Case report 1 y post‐supplementation NR	N = 1 Population: Man, wheel‐chair‐bound; subject was self‐medicated; self‐diagnosed with a pendulum to estimate his deficiencies Exclusion criteria: NA Lost to follow‐up (%): NA Sex (% women): 0 Age (y): 75	Blood concentration of pyridoxine Neurological examination: – Symmetric tetraparesis – Romberg's test – Deep‐tendon reflexes – Touch, temperature, pinprick, vibration, and joint‐position – Skin colour Electrophysiological examination: – Sensorimotor mixed axonal‐demyelination – Distal motor latency (DML) – Motor nerve action potential (MSAP) – Nerve conduction velocity (NCV) – Fibrillation potentials – Signs of reinnervation	Pyridoxine supplementation (+range of other vits): 9.6 g/d Duration (y): 3 Blood pyridoxine (μg/L*): 1850 *Normative range: 40–120 μg/L Method: Self‐reported + blood samples	NA	Neurological examination: Symmetric tetraparesis: distally pronounced muscle weakness Romberg's test: positive Deep‐tendon reflexes: reduced or absent. Touch, temperature, pinprick, vibration and joint‐position: loss at all distal limbs Skin colour: yellowish‐brown Electrophysiological examination: Sensorimotor mixed axonal‐demyelinating polyneuropathy DML (ms): Above normal in both tibial nerves MSAP (mV): Below normal in both tibial nerves, left median nerve, and both radial nerves NCV (ms): Below normal in both tibial and radial nerves Fibrillation potentials: Positive in right tibialis anterior and left vastus medialis Signs of reinnervation: Positive in right tibialis anterior, right flexor pollicis brevis and left vastus medialis Follow‐up (1 y post supplementation): Electrophysiological examinations: DML: Above normal in both tibial nerves, but decreased MSAP: Below normal in both tibial nerves, left median nerve, and both radial nerves, but increased NCV: Below normal in tibial and radial nerves Increased in tibial nerves Fibrillation potentials: All negative Signs of reinnervation: Positive in right tibialis anterior, right flexor pollicis brevis and left vastus medialis Ataxic signs more pronounced than motor signs
Friedman et al. (1986) USA Case report NA NR	N = 1 Population: Woman with good health (general) Lost to follow‐up (%): NA Sex (% women): 100 Age (y): 49	Self‐reported: Numbness bilaterally in great toes Physical examination at hospital: Walking, gait, Romberg's test, Achilles' tendon reflexes, muscle strength Sensory examination: Position sense Temperature Pinprick sensation	Pyridoxine supplementation (g/d): 2 Duration (y): 1 Method: Self‐reported	NA	Self‐reported: Numbness in toes Physical examination at hospital: Diagnosed with sensory peripheral neuropathy Walking: unable to tandem walk Gait: unsteady Romberg's sign test: swaying when eyes closed Achilles' tendon reflexes: absent Muscle strength: normal Sensory examination: Position sense: loss Vibration sense in toes: impaired bilateral sensory deficits Temperature: loss of temperature over feet and toes Pinprick sensation: loss over feet and toes
Stewart et al. (2022) USA RC NA Supported by the Foundation for Peripheral Neuropathy	N = 261 Population sampled: Patients with CIAP enrolled at the Peripheral Neuropathy Research Registry (a multicentre database and biorepository) prior to December 2020 with a complete dataset including plasma vitamin B6 available (within 3 years from ‘study enrolment date’). Cases of vitamin B6 deficiency (0–4.9 μg/L) were excluded. Participants had negative tests for other common peripheral neuropathies aetiologies Lost to follow‐up (%): 0 n = 261 Sex (% women): 44 Age (y): 61.2 ± 13.6	Painful CIAP determined by physician + self‐reported by the participant (questionnaire) Neurological exam: Muscular strength, deep tendon, reflexes, sensory examination findings, gait evaluations, and Romberg test Nerve conduction studies (NCS): Major motor and sensory nerve Intra‐epidermal nerve fibre density measured by skin biopsy (IENFD) History questionnaire: Nature and severity of peripheral neuropathy symptoms, including pain, numbness, weakness, balance, and autonomic symptoms. Also included medication intake Overall neuropathy severity (n = 236): Total Neuropathy Score‐reduced (TNSr), including pinprick sensibility, vibration sensibility, muscular strength, and absence of deep tendon reflexes + degree of paresthesia extension measured by pain and numbness (TNSr 0–5 = mild impairment, 6–9 = moderate, 10–16 = severe)	Vitamin B6, B‐complex or multivitamin (dose NR; n (%)): Normal plasma B6: 28 (15.8) Elevated plasma B6: 38 (33.3) Plasma PLP (μg/L): Overall (mean): 57.7 Normal range (5–50 μg/L), %: 67.8 Elevated (50.1–99.9 μg/L), %: 15.9 Highly elevated (100 μg/L), %: 15.9 With vit B6, B‐complex or multivitamin supplements Normal and elevated plasma B6: 78.8 ± 82.7 Method: Intake: Self‐reported Blood: Mayo Clinic catalogue, Test ID: B6PA	NA	Those taking vit B6 supplement, B‐complex, or a multivitamin had higher plasma vitamin B6 level than those not taking pyridoxine supplements, p = 0.0272 (t‐test) Elevated plasma vitamin B6 levels NS related to any patient‐reported neuropathy sign or symptom, p > 0.05 NCS and IENFD findings: No higher odds for nearly all NCS results, including peroneal or sural velocities or amplitudes, nor for IENFD, in the elevated plasma B6 group vs. normal level group, p > 0.09 The groups with elevated plasma B6 levels were more likely to have an abnormal left peroneal CMAP Amplitude, p = 0.046, but no other relation seen for other peroneal or sural results, p > 0.09 TNSr findings: Physical exam: No higher odds for exam features including ankle and toe strength, vibration sense, deep tendon reflexes, pinprick border, or gait abnormality in the elevated vitamin B6 groups vs. normal levels, p > 0.1 TNSr score: No higher odds for mild vs. moderate or severe TNSr, p = 0.561 Self‐report: There were no differences in frequency or severity of patient‐reported pain, pain types (i.e. sharp, hot, or deep pain), or numbness, p > 0.1 All tests adjusted for age and time elapsed since the onset of symptoms (in years)
Anonymous (2020) Netherlands and France Case series NA NR	N = 115 Population: Netherlands: 90 cases with peripheral sensory, motor, and autonomic nervous system neuropathy from the Netherland Pharmacovigilance Centre (1991–2017) France: 25 reports on neuropathy from the French Health Products Agency (1986–2018) % lost to follow up: NA n, Netherlands: 90 France: 25 Sex (% women): Netherlands: 80 France: 56 Age (y): Netherlands (mean (range)): 53 (3–85) France (range): 25–92	Netherlands: Adverse drug reaction reports linked to vit B6 intake France: Reports of neuropathy linked attributed to vitamin B6‐containing drugs	B6 supplementation: Netherlands (mg/tablet; dose in tablet known for 63 cases, usually at least 25 mg and > 50 mg in 1/3 of cases): 1.4–100 (number of daily tablet intake NR) France (mg): – 5–250 (amount in culprit drugs, daily dose NR) – Vitamin B6 doses taken as combinations of vitamins and minerals: < 10 cases Duration: B6 supplementation: Netherlands: average 2 y France: 8 d – 4 y Type of vitamer: NR European normative range: 0.3–2 mg/day	Neuropathy, n Netherlands : Peripheral sensory, motor and autonomic nervous system neuropathy: 90 France: Neuropathy: 25	Netherlands: Cases had either peripheral neuropathy, paraesthesia, hypoesthesia, neuropathic pain, chronic polyneuropathy and burning sensations or muscle weakness Symptoms regressed in 30 patients after ending B6 supplementation France: Cases had either neuritis, polyneuritis, neuropathy, heaviness of the limbs, distal paraesthesia, motor, sensory or sensorimotor peripheral neuropathy, inability to walk, muscle pain or cutaneous burning sensation Heterogeneity: In many cases participants were taking other substances known to increase risk of neuropathy
Van Hunsel et al. (2018) Netherlands Case series NA NR	N = 139 Population: All patients with adverse drug reactions (ADRs) related to neuropathy and health supplements that contain vitamin B6 reported to the Netherlands Pharmacovigilance Centre Lareb from 1991 (establishment of the center) until July 2017 Lost to follow‐up (%): NA n = 90 Sex (% women): 80 Age (y): 53.2 ± 15.7 (3–85)	Data extracted from the database as an adverse drug reaction coded with a MedDRA preferred term (PT) within the MedDRA version 20.1 standardised MedDRA query (SMQ) ‘peripheral neuropathy’. Symptoms were self‐reported, and some symptoms could be neuropathy in general and not specifically peripheral neuropathy. Many patients were seen by a neurologist, but few diagnostic tests were reported. Some patients reported symptoms, but electromyogram was normal Causality assessed using the Bradford Hill criteria (strength of association, consistency of the cases, specificity, temporality, biological gradient, coherence, experiment, analogy)	Vitamin B6 intake from supplements (mg/tablet or %DRV): 1.4–100 or 200–400 *number of tablets taken daily NR. Some cases took > 1 tablet/d with a dose > 100 mg/d *In 38 cases, vitamin B6 dose reached ≥ maximum acceptable daily intake of 25 mg for adults, and 22 of these cases had a dosage ≥50 mg. The dose was unknown in 27 cases Latency period (n = 57; mean d [y] ± SD): 807 [2.2] ± 1461 [4.0] (‘minutes after start’ ‐ [23]) ≤ 2 mo: n = 2 Serum vit B6 (n = 36; nmol/L, mean, median (range)): 907, 945 (88–4,338) (reference 51–183 nmol/L) Type of vitamer: NR Method: NR	NA	NS correlation (Pearson correlation r = − 0.876, p = 0.65) between vit B6 dose and serum levels (n = 29), no dose–response analysis was possible – The highest observed serum vit B6 level was caused by 50 mg/d of pyridoxine supplementation for 2 years – Another case used 75 mg/day for 2.5 months and reached a serum level > 500 nmol/L. After 1 month of withdrawal, the serum level decreased to 261 nmol/L and symptoms improved Recovery seen 2.5 y after cessation of vitamin supplements after vit B6 intake for 3.5 y (dose NR) Self‐reported symptoms: Case 1: Tingling of legs aggravating to muscle weakness of lower limb, numbness of arm and thumb and neuropathic pain (‘numbness in leg and balance difficulty’) Case 2: Strange feeling in right thigh, sensory disturbance, muscle twitching, involuntary muscle movements at rest, burning pain in both knees and fibula cups, burning pain, mushy feeling buttocks, and painful hips after sleep Case 3: Coldness of limbs and tingling feet, aching feet, very difficult to walk (= symptoms of small fibre peripheral neuropathy) Other cases: increased and burning sensation in the foot and lower leg + numbness of the big toe’ + tingling of lower legs Causality conclusion: ‘It is plausible for the B6 supplements to have caused complaints such as neuropathies. This is especially the case with higher dosages and prolonged use, but dosages < 50 mg/day also cannot be excluded’. ‘The dosage and timing at which patients are prone to develop adverse reactions is subject to a patient's individual susceptibility’.
Kaur et al. (2014) NR Case report 3 mo post‐supplementation NR	N = 1 Population: One case with progressive distal lower extremities weakness and paraesthesia 2 weeks following an episode of diarrhoea Exclusion criteria: NA Lost to follow‐up (%): NA Sex (% of women): 100 Age (y): 44	1. Physical examination 2. Electrodiagnostic studies	Blood PLP, μg/L: 116 Blood PA, μg/L: 37 Vit B6 intake, mg: Reported as megadose, but mg NR Duration: 1 year Normative range: PLP: 5–30 μg/L, PA: 3–30 μg/L Method: Blood sample and self‐reported B6 intake	NA	1. Weakness of bilateral extensor hallucis longus and foot plantar flexion, hypoflexia at the ankles bilaterally and sensory loss to all primary modalities up to bilateral mid calves 2. Subacute sensorimotor axonal polyneuropathy Dorsal root ganglion cells and subsequent degeneration of both sensory peripheral nerve fibres and dorsal column axons = sensory neuropathy/neuronopathy After stopping vit B6 supplementation for 3 mo: Mild improvement in symptoms but motor weakness persisted

Mean ± SD (standard deviation), unless specified otherwise.

BMI: body mass index; CC: case–control; CIAP: chronic idiopathic axonal polyneuropathy; CS: cross‐sectional; CTS: carpal tunnel syndrome; d: day; DRV: dietary reference value; hr: hour; MM: median motoneuropathy; mo: month; MRC: Medical research Council; NA: not applicable; NR: not reported; NS: non‐significant; PA: pyridoxic acid; PC: prospective cohort; PLP: pyridoxal‐5′‐phosphate; RC: retrospective cohort; RDI: recommended daily intake; UK: United Kingdom; USA: United Sates of America; vit: vitamin; y: year; wk/wks: week/s